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Steroid 5α-reductase (5αR) converts testosterone into dihydrotestosterone (DHT), a potent androgen driving prostate cell proliferation via the androgen receptor (AR). Both 5αR and AR play crucial roles in androgen-mediated disorders, making them key therapeutic targets in drug development. Current treatments target these enzymes individually and often cause significant side effects, highlighting the need for safer alternatives. Through in silico screening, 13 pyrrolizidine alkaloids of Heliotropium indicum (HI) were assessed for their inhibitory potential against 5αR and AR. Using machine learning, six alkaloids showed promising pIC50 values. The accuracy of the models was assessed using key statistical parameters, including the score, correlation coefficient for training sets (R2), correlation coefficient for test sets (Q2), standard deviation (SD), and root mean square error (RMSE). For 5αR, the results were 0.763 (R2), 0.781 (Q2), 0.748 (score), 0.362 (SD), and 0.832 (RMSE), while for AR, the values were 0.817 (R2), 0.783 (Q2), 0.713 (score), 0.427 (SD), and 0.782 (RMSE), indicating reliability. Europine-N-oxide (-10.27 kcal/mol) and Heliotridine-N-oxide (-9.72 kcal/mol) displayed stronger 5αR binding than Finasteride, while Heliotrine (-10.09 kcal/mol) and Europine-N-oxide (-8.76 kcal/mol) outperformed Enzalutamide in AR binding. Key hydrogen bonds and MD simulations confirmed stable interactions. Pharmacokinetic screening revealed favorable drug-like profiles, including good solubility and absorption with minimal CYP enzyme inhibition. These findings suggest that HI alkaloids are promising multi-target inhibitors for BPH treatment, warranting further in vivo validation and optimization. [ABSTRACT FROM AUTHOR]

In the realm of epigenetic regulation, Protein arginine deiminase 2 (PAD2) stands out as a therapeutic target due to its significant role in neurological disorders, rheumatoid arthritis (RA), multiple sclerosis (MS), and various cancers. To date, no in silico studies have focused on PAD2 for lead compound identification. Therefore, we conducted structure-based pharmacophore modeling, virtual screening, molecular docking, molecular dynamics (MD) simulations, and essential dynamics studies using PCA and free energy landscape analyses to identify repurposed drugs and selective inhibitors against PAD2. The best pharmacophore model, 'Pharm_01,' had a selectivity score of 10.485 and an excellent ROC curve quality of 0.972. Pharm1 consisted of three hydrogen bond donors (HBD) and two hydrophobic (Hy) features (DDDHH). A virtual screening of about 9.2 million compounds yielded 2575 hits using a fit value threshold of 2.5 and drug-likeness criteria. Molecular docking identified the top ten molecules, which were verified using MD simulations. Stability was verified using MM-PBSA studies, whereas conformational differences were investigated using PCA and free energy landscape analyses. Two hits (Leads 1 and 2) from the DrugBank dataset showed promise for repurposing as PAD2 inhibitors, while one hit compound (Lead 8) from the ZINC database emerged as a novel PAD2 inhibitor. These findings indicate that the discovered compounds may be potent PAD2 inhibitors, necessitating additional preclinical and clinical research to produce viable treatments for cancer and neurological disorders. [ABSTRACT FROM AUTHOR]

Surface roughness control of end products is increasingly becoming significant, especially with the miniaturization trends in the semiconductor industry. Ultra-thin amorphous carbon (a-C) films offer a prime solution to optimize surface roughness due to their outstanding characteristics. In this study, hydrogenated a-C films are deposited on two-dimensional quartz plates and three-dimensional quartz molds to evaluate the growth mechanisms and changes in the surface roughness, which is supported by molecular dynamics simulations. Results reveal that surface roughness encounters multiple variations until it reaches stable values. These fluctuations are categorized into four different stages which provide a concrete understanding of various growing mechanisms at each stage. Different behavior of the atoms in the top layers is recorded in the cases of normal and grazing incidents of carbon atoms. Lower surface roughness values are obtained at low-angle deposition. Interestingly, surface smoothing is attained on the sidewalls of the nanotrench mold where the deposition occurs with high incident ion angles. [ABSTRACT FROM AUTHOR]

The 'gas‒liquid‒solid' mechanism annealing method was used to create a superhydrophobic boron nitride nanotube (BNNT) stainless steel mesh in a tube furnace at 1250 °C in an NH3 environment. Fe powder was used as a catalyst, and B:B2O3 = 4:1 was used as the raw material. The water droplets on the surface of the superhydrophobic material had a contact angle of approximately 150° and a slide angle of approximately 3°. By using molecular dynamics (MD) simulation technology, a three-dimensional braided physical model of nanodroplets and superhydrophobic BNNT mesh surfaces with the same contact angle and rolling angle was prepared via the function weaving method. The Weber number (We) was used as the entrance point to establish the relationship between macroscale experimental studies and nanoscale MD simulation analysis on the basis of these efforts. A study was conducted on the dynamic behaviour of droplets impacting a superhydrophobic BNNT filter surface. We suggest that the wettability, substrate structure, and impact velocity are connected to the impact dynamic behaviour of droplets on the basis of the data obtained at various scales. The findings demonstrate that when the droplet impact velocity increases, several droplet phenomena—such as impact–rebound, impact–spread–rebound, and impact–spread–breaking–polymerisation–spatter—appear on the substrate surface sequentially. The mechanism of impact behaviour at various scales is explained in light of these events. Furthermore, a better theoretical model is proposed to assess the droplet wetting transition at the nanoscale. This model accurately predicts the boundary Weber number that starts the wetting transition. Moreover, the connections among the impact velocity, spreading diameter, and contact time (or We) are examined. The tendencies found via MD simulations match the outcomes of the experiments. Our discoveries and outcomes broaden our understanding of how droplet impact affects the dynamic behaviour of superhydrophobic surfaces. A scientific foundation for examining the dynamic behaviour of droplets is provided by combining simulations and experiments. [ABSTRACT FROM AUTHOR]

The Hepatitis C virus (HCV) is a blood-transmitted virus responsible for persistent inflammation, presenting a substantial worldwide health challenge. HCV, characterized by a positive-stranded ribonucleic acid genome, possesses an intricate genetic makeup encoding both structural and non-structural proteins, crucial for sustaining its life cycle. The Direct Acting Antivirals have revolutionized the treatment landscape of HCV promoting higher Sustained Virological Response rates. Despite significant advancements in treatment, no vaccines are currently available against HCV. The development of effective HCV vaccines becomes challenging as the genetic diversity of HCV virus and its complex nature of the immune response required for protection. In this work, the immunoinformatics methods were utilized to develop a multiple-epitope-based vaccine towards an effective treatment against the viral HCV polyprotein. The vaccine was constructed by T-cell epitopes extracted from the viral polyprotein of HCV genotypes 1a and 1b. The vaccine was highly antigenic, non-toxic, and non-allergenic. Effective binding of the designed vaccine construct was studied by forming complexes with the human immune Toll-Like Receptors; TLR3 and TLR8. The MD simulation of these receptor-vaccine complexes were performed for 50ns and the immunological simulation of modeled vaccine in presence of receptors for 365 days timeline validated the stability of the constructed vaccine. The in-silico vaccine construct developed from this work might be beneficial as prophylactic measures against the HCV variants, if explored further in in vivo and in vitro methods. Consequently, this research outcome is presumed to have implications in the development of safer and more efficient vaccines for lethal diseases. [ABSTRACT FROM AUTHOR]

Citrobacter koseri causes infection in people who are immunocompromised. Without effective antibiotics, these infections can become severe and life-threatening, so effective drugs are essential to treat these infections. Utilizing subtractive genomics, 2699 ORFs were predicted and translated into amino acid sequences. Metabolic pathway analysis and subcellular localization helped define the roles of key bacterial proteins. Two druggable proteins, WP_012000829.1 and WP_275157394.1, were discovered as promising targets. Alpha Fold provided 3D structures, and a library of 1600 echinoderm metabolites was docked against these proteins, with Ampicillin, Levofloxacin, and Doxycycline as controls. Notably, CMNPD13085 and CMNPD15632 exhibited the highest binding affinities for WP_012000829.1 and WP_275157394.1, respectively. Molecular dynamics simulations and MM-GBSA binding free energy complemented docking results. However, acknowledging the reliance on computational validations, the study emphasizes the need for essential in-vitro research to transform these potential inhibitors into therapeutic drugs. [ABSTRACT FROM AUTHOR]

Antibiotics have played a crucial role in significantly reducing the incidence of tuberculosis (TB) infection worldwide. Even before the mid‐20th century, the mortality rate of TB onset within five years was around 50 %. So, the introduction of antibiotics has changed the scenario of TB from a serious threat to a manageable one. However, the emergence of resistance to anti‐TB drugs poses a significant challenge. So, to overcome this situation the therapeutic approaches and drug targets need to be reformed. This study focused on finding potential inhibitors by targeting Pantothenate Synthetase, a crucial enzyme for Mycobacterium tuberculosis (Mtb) survival, through computational drug discovery methods. Molecular docking and virtual screening were employed to identify potential inhibitors from Diverse‐lib. Four compounds, namely CID2813602, 24357538, CID753354, and CID4798023, exhibited strong binding energies and stable interaction with the target protein. Further assessment of these compounds through MD simulation and Post MD simulation showed significant dynamic stability. The minimum energy transition calculated using the free energy landscape analysis of these compounds when docked with Pantothenate Synthetase confirmed the stability of each complex due to its minimum energy production. The free binding energy calculation of each complex also showed the intramolecular interaction contributes to the strong binding affinity of the compounds within the enzyme's active site clarifying their mechanisms of action. This research showcases the effectiveness of computational methods in promptly identifying potential anti‐TB drugs, paving the way for future experimental validation and optimization. It holds promise for the development of new treatments targeting drug‐resistant TB strains. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) is a well‐known member of the PPAR family and a potential target for the treatment of various disorders. Herein, we present the design and synthesis of various 6‐aryl‐4‐sec.amino‐2‐oxo‐2H‐pyran‐3‐carbonitrile derivatives and functionalized thieno[3,2‐c]pyran‐2‐ones, derived from ketene dithioacetal. Then all the synthesized compounds were docked for their activity as PPAR‐γ to predict the binding mechanism and affinities regarding rosiglitazone and muraglitazar. Our studies revealed that three compounds 10 e, 10 f, and 10 h showed significant binding affinities, with energy ranges comparable to standard drugs rosiglitazone and muraglitazar. The docking conformation studies revealed that the selected compounds nicely interact with PPAR‐γ in the ligand binding domain with positive predictive values. We also performed molecular dynamics of the most potent compounds to validate the result. Our results indicate that these novel compounds are potential PPAR‐γ ligands, offering new possibilities for therapeutic applications. This study underscores the potential of these synthesized compounds in the development of novel PPAR‐γ agonists. [ABSTRACT FROM AUTHOR]

Binding site flexibility and dynamics strongly affect the ability of proteins to accommodate substrates and inhibitors. The significance of these properties is particularly pronounced for proteins that are inherently flexible, such as cytochrome P450 enzymes (CYPs). While the research on human CYPs provides detailed knowledge on both structural and functional level, such analyses are still lacking for their plant counterparts. This study aims to bridge this gap. We developed a novel computational pipeline consisting of two steps. Firstly, we use molecular dynamics (MD) simulations to capture the full conformational ensemble for a certain plant CYP. Subsequently, we developed and applied a comprehensive methodology to analyze a number of binding site properties—size, flexibility, shape, hydrophobicity, and accessibility—using the fpocket and mdpocket packages on MD-generated trajectories. The workflow was validated on human CYPs 1A2, 2A6, and 3A4, as their binding site characteristics are well known. Not only could we confirm known binding site properties, but we also identified and named previously unseen binding site channels for CYPs 1A2 and 2A6. The pipeline was then applied to plant CYPs, leading to the first categorization of 15 chosen plant CYPs based on their binding site's (dis)similarities. This study provides a foundation for the largely uncharted fields of plant CYP substrate specificity and facilitates a more precise understanding of their largely unknown specific biological functions. It offers new insights into the structural and functional dynamics of plant CYPs, which may facilitate a more accurate understanding of the fate of agrochemicals or the biotechnological design and exploitation of enzymes with specific functions. Additionally, it serves as a reference for future structural–functional analyses of CYP enzymes across various biological kingdoms. [ABSTRACT FROM AUTHOR]

N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC), a quaternized chitosan derivative, has been shown to exhibit a broad spectrum of antimicrobial activity, especially against bacteria and enveloped viruses. Despite this, molecular docking studies showing its atomic-level mechanisms against these microorganisms are scarce. Here, for the first time, we employed molecular docking analyses to investigate the potential antibacterial activity of HTCC against Staphylococcus aureus and its antiviral activity against human immunodeficiency virus 1 (HIV-1). According to the findings, HTCC exhibited promising antibacterial activity with high binding affinities; however, it had limited antiviral activity. To validate these theoretical outcomes, experimental studies were conducted. Different derivatives of HTCC were synthesized and characterized using NMR, XRD, FTIR, and DLS. The in vitro assays validated the potent antibacterial efficacy of HTCC against S. aureus, whereas the antiviral studies did not show good antiviral activity. However, our research also revealed a promising avenue for further exploration of the antimicrobial activity of HTCC nanoparticles (NPs), since, thus far, no studies have been conducted to show the antiviral activity of HTCC NPs against HIV-1. The nanosized HTCC exhibited superior antiviral performance compared to the parent polymers, with complete (100%) inhibition of HIV-1 viral activity at the highest tested concentration (0.33 mg/mL). [ABSTRACT FROM AUTHOR]

Plumbene, the new 2D structure of lead, single-layered with a hexagonal arrangement of atoms draws the attention of researchers around the globe. We have designed a plumbene sheet using multi-scale modelling i.e. nonequilibrium molecular dynamics (NEMD) simulation methods to determine the electrical properties of plumbene. The effects of varying sample sizes and temperatures on the electrical properties of plumbene using NEMD are studied here. It is observed from 298 K to 318 K electrical conductivity of plumbene ranges from 2.7792 × 10−14 S/m to 1.2012 × 10−13 S/m, with a dwindling nature. Almost static electrical resistivity from 298 K to 378 K is noticed, afterwards a sudden sharp increase till 398 K. The Lorenz number of plumbene from 298 K to 318 K shows reverse results with its electrical conductivity under similar experimental conditions. The electrical conductivity of plumbene sheets at 298 K with 600Å to 1050Å ranges from 0.17794 × 10−14 S/m to 4.7696 × 10−14 S/m. Only at 750Å sample size is a sharp jump is noticed. A reverse trajectory is observed for both electrical resistivity and Lorenz number of plumbene sheet samples. In these two cases, the sharp jump is observed at 1000Å. Our results will be helpful for the effective utilisation of plumbene in targeted applications of electrical engineering fields. [ABSTRACT FROM AUTHOR]

The COVID-19 caused by the SARS-CoV-2 virus has escalated into a global pandemic, urgently necessitating effective treatments. Tremendous research of the SARS-CoV-2 main protease have enabled insight understanding of its mechanism and potential inhibitors. Due to its crucial role in viral replication, the protease is considered an attractive target for antiviral therapy. This study aimed to identify novel potent inhibitors of main protease protein by repurposing i-Motif (iM) binding compounds from the G4LDB database. iM ligands are known for their ability to stabilise iM structures in DNA, and their repurposing as protein inhibitors is an alternative therapeutic approach. To achieve this, we performed in silico studies with six iM binding compounds. Molecular docking, molecular dynamics (MD) simulations and MM/GBSA binding free energy analysis revealed favourable conformational stability and superior binding affinity of the three proposed iM ligands, including iML0042 (−59.91 ± 3.82 kcal/mol), iML0043 (−56.37 ± 3.87 kcal/mol), and iML0094 (−84.68 ± 3.40 kcal/mol), to SARS-CoV-2 Mpro variants compared to the reference inhibitor nirmatrelvir (−34.35 ± 3.74 kcal/mol). The results suggested that repurposing iM ligands as protease inhibitors is a promising strategy. Our findings revealed significant candidate inhibitors and are recommended for further development as potential protease inhibitors against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Bruton's Tyrosine Kinase (BTK), a soluble tyrosine kinase plays an essential role in the growth, development, and signalling of B cells. It is a non-receptor kinase that is crucial for leukemic cell survival, proliferation, and oncogenic signalling in many B cell malignancies. The enhanced metastasis caused by BTK expression may be reduced by BTK inhibitors, which also have powerful therapeutic effects. The goal of the study is to identify potential inhibitors which have good binding affinity with BTK. The current study also aims to investigate the expression pattern and the prognostic significance of BTK across all cancer types. Interestingly, it was found that BTK was highly overexpressed in numerous cancer types including; clear cell renal carcinoma, glioblastoma, head and neck, liver and breast cancer. BTK was found to reduce the relapse-free and overall survival rate. Furthermore, using in silico approach two structural analogues of Pirtobrutinib namely; 163207918 and 129269825 that bind to BTK with higher affinity were identified. Using drug-likeness analysis the therapeutic possibility of screened Pirtobrutinib analogues were evaluated. The Molecular docking and dynamic analysis revealed that the new Pirtobrutinib analogues could be potent inhibitors with higher binding affinity and stability in comparison with the parent compound. In conclusion, after preclinical and clinical research, the identified analogues may open the door for their prospective use in cancer therapy. [ABSTRACT FROM AUTHOR]

The activation of the Neuraminidase 3 (NEU3) enzyme has been associated with the hyperphosphoryla-tion of Epidermal Growth Factor Receptor (EGFR) in Nonsmall Cell Lung Carcinoma (NSCLC). Existing EGFR inhibitors (such as gefitinib, erlotinib, lapatinib, icotinib, afatinib and osimertinib) reduce the hyperactivation of downstream signaling pathways (Akt, Mapk, Jak-Stat, Plc) but fail to completely abolish EGFR hyperphosphorylation. Therefore, co-targeting NEU3 and EGFR presents a greater potential to be used as a combinatorial therapy for NSCLC. This study employs structure guided approaches to elucidate the binding hypothesis of NEU3 and EGFR inhibitors. Toward this, important 3D features associated with high inhibitory potency of NEU3, and EGFR modulators were identified through SAR. The triazole substitution in acetamide dihydropyran carboxylic acid derivatives is mainly responsible for improved inhibitory potency against NEU3. Therefore, the hydrophobic (ϕ -H) interaction with the benzene ring and hydrogen bonding with the hydroxyl group of triazole are critical for designing new NEU3 modulators. Molecular Dynamics (MD) simulation studies demonstrate the stability of hydrogen bonding interactions of highly active NEU3 inhibitors with Pro66, Gly199 and Glu410 residues. Similarly, pyrimidine ring of EGFR inhibitors forms stable hydrogen bonds with Lys721 and Asp831 residues, contributing to their inhibitory potency. Our findings suggest that incorporating these identified 3D features associated with triazole and pyrimidine substitutions into a suitable scaffold could be a valuable strategy for developing a new generation of NEU3 and EGFR modulators. This approach offers a potential multi-targeted therapy for NSCLC patients. This study explores co-targeting NEU3 and EGFR for treating NSCLC by identifying key 3D features that enhance inhibitor potency. The research highlights that triazole substitutions improve NEU3 inhibition, while pyrimidine rings contribute to EGFR inhibition through stable hydrogen bonding and hydrophobic interactions. By integrating the identified interactions associated with the potent triazole and pyrimidine substitutions into a new scaffold may provide a promising approach for developing multi-targeted therapies for NSCLC. [ABSTRACT FROM AUTHOR]

Helicobacter pylori is a Gram-negative bacterium that infects the human gastrointestinal mucosa and is a significant human pathogen, affecting 50% of the world's population. Multidrug Efflux Pump mepA from the MATE family of proteins acts as a potential efflux pump target in Helicobacter pylori which exports multiple drugs outside the Helicobacter pylori and consists of 417 amino acids. This study aimed to identify potential inhibitors of the multidrug efflux pump mepA in Helicobacter pylori using in-silico approaches that employed molecular docking, drug-likeness evaluation, density functional theory [DFT], molecular dynamics (MD) simulations, and free energy calculations to analyze, the interactions between phytochemicals compounds and mepA protein. The best compounds exhibiting the highest binding affinities toward mepA were selected among all the screened phytochemical compounds from the database. Overall, this research identified three promising natural compounds Hinokiflavone (− 10.9 kcal/mol), Ipomine (− 10.7 kcal/mol), and Lupinisoflavone M (− 10.5 kcal/mol) from 30 top compounds based on binding affinity score, which demonstrated remarkable binding affinities toward mepA through molecular docking, suggesting their potential to block the efflux pump and potentiate antibiotic action with the potential to inhibit the multidrug efflux pump mepA in Helicobacter pylori. Besides, we select one complex for 3 compounds for an analysis of DFT and calculate the stability of protein and protein–ligand complex by Molecular Dynamics simulation along with this we calculate the binding free energy for the complex's protein for selected Lupinisoflavone M complex (− 98.948 kJ/mol). The study highlights the promising capacity of the selected compounds to inhibit the mepA efflux pump, potentially paving the way for developing novel therapeutic strategies against multidrug-resistant pathogens. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial DNA variants are significant contributors to cancer progression, as evidenced by numerous findings. This study focuses on characterizing mitochondrial DNA mutations in colorectal cancer progression and their potential as biomarkers. Methodology: Next generation sequencing technology was employed to analyze mitochondrial DNA variants in tumor and adjacent normal tissues from 25 patients with colon/rectal cancer. In silico prediction tools (SIFT, Polyphen2, Mutation Assessor, and SNP&GO) were utilized to assess the pathogenicity of these variants. Additionally, homology modeling of mutated protein structures was conducted, and molecular dynamic simulations were performed to assess the impact of mutation on protein function. Results: Eighteen variants were identified across most tumor tissue samples, located in genes from Complex I, IV, and V. Among the identified variants, the V302M and S461 mutations in the MT-ND5 gene and L137F and L220P mutations in the ATP6 gene were predicted to be deleterious, potentially affecting protein function. 3D structural analysis of both wild-type and mutant proteins of MT-ND5 revealed changes in flexibility for the V302M and S461G mutations. The MT-ATP6 mutations L135F and L220P disrupt the interactions with surrounding residues and affect the overall function of protein. Further changes in protein dynamics of the mutated proteins by molecular dynamic simulations also indicate the effects; the mutations have on protein function. Conclusion: MT-ND5 and MT-ATP6 variants could serve as potential biomarkers and drug targets in colorectal cancer. This study underscores the significance of mitochondrial DNA variants in cancer progression. [ABSTRACT FROM AUTHOR]

Whipple disease caused by Tropheryma whipplei a gram-positive bacterium is a systemic disorder that impacts not only the gastrointestinal tract but also the vascular system, joints, central nervous system, and cardiovascular system. Due to the lack of an approved vaccine, this study aimed to utilize immunoinformatic approaches to design multiepitope -based vaccine by utilizing the proteomes of five representative T. whipplei strains. The genomes initially comprised a total of 4,844 proteins ranging from 956 to 1012 proteins per strain. We collected 829 nonredundant lists of core proteins, that were shared among all the strains. Following subtractive proteomics, one extracellular protein, WP_033800108.1, a WhiB family transcriptional regulator, was selected for the chimeric-based multiepitope vaccine. Five immunodominant epitopes were retrieved from the WhiB family transcriptional regulator protein, indicating MHC-I and MHC-II with a global population coverage of 70.61%. The strong binding affinity, high solubility, nontoxicity, nonallergenic properties and high antigenicity scores make the selected epitopes more appropriate. Integration of the epitopes into a chimeric vaccine was carried out by applying appropriate adjuvant molecules and linkers, leading to the vaccine construct having enhanced immunogenicity and successfully eliciting both innate and adaptive immune responses. Moreover, the abilityof the vaccine to bind TLR4, a core innate immune receptor, was confirmed. Molecular dynamics simulations have also revealed the promising potential stability of the designed vaccine at 400 ns. In summary, we have designed a potential vaccine construct that has the ability not only to induce targeted immunogenicity for one strain but also for global T. whipplei strains. This study proposes a potential universal vaccine, reducing Whipple's disease risk and laying the groundwork for future research on multi-strain pathogens. [ABSTRACT FROM AUTHOR]

Expanding the protein fold space beyond linear chains is of fundamental significance, yet remains largely unexplored. Herein, we report the creation of seven topological isoforms (i.e., linear, cyclic, knot, lasso, pseudorotaxane, and catenane) from a single protein fold precursor by rewiring the connectivity of secondary structure elements of the SpyTag-SpyCatcher complex and mutating the reactive residue on SpyTag to abolish the isopeptide bonding. These topological isoforms can be directly expressed in cells. Their topologies were confirmed by combined techniques of proteolytic digestion, fluorescence correlation spectroscopy (FCS), size-exclusion chromatography (SEC), and topological transformation. To study the effects of topology on their structures and properties, their biophysical properties were characterized by differential scanning calorimetry (DSC), heteronuclear single quantum coherence nuclear magnetic resonance spectroscopy (HSQC-NMR), and circular dichroism (CD) spectroscopy. Molecular dynamics (MD) simulations were further performed to reveal the atomic details of structural changes upon unfolding. Both experimental and simulation results suggest that they share a similar, well-folded hydrophobic core but exhibit distinct folding/unfolding dynamic behaviors. These results shed light onto the folding landscape of topological isoforms derived from the same protein fold. As a model system, this work improves our understanding of protein structure and dynamics beyond linear chains and suggests that protein folds are highly amenable to topological variation. [ABSTRACT FROM AUTHOR]

Due to the high toxicity, poor efficacy and resistance associated with current anti-breast cancer drugs, there's growing interest in natural products (NPs) for their potential anti-cancer properties. Computational modelling of NPs to identify key structural features can aid in developing novel natural inhibitors. In this study, we developed statistically significant QSAR models based on NPs from the NPACT database, which have shown potential anticancer activity against the MCF-7 cancer cell lines. All the developed QSAR models were statistically robust, meeting both internal (R2 = 0.666–0.669, R2adj = 0.657–0.660, Q2Loo = 0.636–0.638) and external (Q2Fn = 0.686–0.714, CCCext = 0.830–0.847) validation criteria. Consequently, they were utilized to virtually screen a series of NPs from the COCONUT database in the search for novel natural inhibitors. Molecular docking studies were conducted on the identified compounds against the human HER2 protein (PDB ID: 3PP0), which is a crucial target in breast cancer. Molecular docking analysis demonstrated that compounds 4608 and 2710 achieved the highest docking scores, with CDOCKER interaction energies of -72.67 kcal/mol and − 72.63 kcal/mol respectively. Compounds 4608 and 2710 were identified as the most promising candidates upon performing triplicate 100 ns MD simulation study using the CHARMM36 force field. DFT studies was performed to evaluate their stability and reactivity as potential drug molecules. This research contributes to the development of new natural inhibitors for breast cancer. [ABSTRACT FROM AUTHOR]

Cervical cancer begins in the cells lining the cervix and is caused by persistent infection with certain types of human papillomavirus (HPV). Initially, it has no symptoms, and later it causes pelvic pain, abnormal vaginal bleeding, and pain during intercourse. It is the fourth-ranked cancer among women, and many women die from cervical cancer every year, particularly in low-income countries and the majority could be prevented with early detection and treatment. In this study, we have taken Cervical Cancer DNA Replication and Repair-Related Protein with the PDBID- 3H15, 5VBN, and 6NT9 and performed the multitargeted molecular docking with the FDA-approved drug library using HTVS, SP and XP docking. Then, the poses were filtered with MM\GBSA for proper computations of free energy, identified a multitargeted inhibitor Droxidopa with docking and MM\GBSA scores ranging from − 5.559 to − 6.835 Kcal/mol and − 26.04 to − 37.33 Kcal/mol, respectively. We also performed interaction fingerprints revealing 2VAL, 2LYS, 1ALA, 1ARG, 1ASN, 1CYS, 1GLN, 1GLU, 1ILE, 1MET, 1PHE, 1PRO, 1SER, and 1THR were most interacted residues and computed the ADMET properties with QikProp and DFT with Jaguar, which supported the study and compounds' suitability. Moreover, we performed the 100ns MD simulation in water, showing the controlled deviation and fluctuations of the residues with many interactions, and MM\GBSA was performed with the same trajectories, showing a better understanding of each frame's total complex and binding-free energy. The whole study favours droxidopa as an inhibitor of cervical cancer DNA Replication and Repair-Related Proteins—however, experimental studies are needed before use. [ABSTRACT FROM AUTHOR]

Highlights A novel organic coating was created by dispersing solvent‐free covalent graphene oxide nanofluids (GO NFs) into a polyimide (PI) matrix. The tribological properties of GO NFs/PI composite coatings was tested against ball‐on‐disk tribometer. Even a low loading of GO NFs significantly improve the tribological properties of PI. MD simulation and nanoindentation tests reveal that GO NFs adsorbs the PI molecular chains, enhancing the composites' mechanical properties. Moreover, a stable tribofilm develops on the steel ball surface lubricated with the GO NFs/PI composite coating, with analyses indicating that the GO NFs promote its growth. The enhancement of mechanical properties and the formation of this tribofilm are essential for the improved tribological performance of the composite. This research aims to contribute to the development of novel PI composite coatings with superior anti‐friction and wear‐resistant properties. The GO NFs exhibited excellent dispersion stability and tribological properties. Novel GO NFs/PI composite coating with significantly enhanced tribological properties. A carbon‐based tribofilm forms on the steel ball. The strengthening mechanisms of composites were revealed by MD simulation. [ABSTRACT FROM AUTHOR]

Molecular dynamics (MD) simulation of the green ionic liquid [C₄mim][PF₆] mixed with polar benzonitrile (BNZ) solvent provides detailed insights into their structural and dynamic properties, essential for electrochemistry and materials science applications. The simulations we carried out at varying mole fractions (XBZN) reveal the mixtures' physical, structural, and dynamic properties, with radial, spatial, and combined distribution functions, highlighting the effective interaction through H-bonding involved. The simulation indicates that BZN stacks on the cation butyl tail, providing a significant explanation for the unique experimental observations (following). Adding BZN causes the mixture's liquid dynamics to increase linearly at low XBZN and exponentially at high XBZN, with a notable singular transition at 0.5XBZN. Comprehensive efforts were made to verify and support experimental sum frequency generation (SFG) spectroscopy by simulating the surface structure of the mixtures. Consequently, the simulated BZN stacking structure explains (1) the absence of the C≡N vibrational mode in the SFG spectrum for XBZN < 0.8, and (2) the gradual diminishing of the CH3 SFG signal, which disappears as XBZN approaches 0.5. Finally, this research removes a persistent ambiguity, proving that only the molecular moieties on the surface generate the SFG vibrational signal, while those in the subsurface do not. [ABSTRACT FROM AUTHOR]

The previously introduced workflow to achieve an energetically and structurally optimized description of frontier bonds in quantum mechanical/molecular mechanics (QM/MM)‐type applications was extended into the regime of computational material sciences at the example of a layered carbon model systems. Optimized QM/MM link bond parameters at HSEsol/6‐311G(d,p) and self‐consistent density functional tight binding (SCC‐DFTB) were derived for graphitic systems, enabling detailed investigation of specific structure motifs occurring in graphene‐derived structures via quantum‐chemical calculations. Exemplary molecular dynamics (MD) simulations in the isochoric‐isothermic (NVT) ensemble were carried out to study the intercalation of lithium and the properties of the Stone–Thrower–Wales defect. The diffusivity of lithium as well as hydrogen and proton adsorption on a defective graphene surface served as additional example. The results of the QM/MM MD simulations provide detailed insight into the applicability of the employed link‐bond strategy when studying intercalation and adsorption properties of graphitic materials. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most commonly diagnosed cancer and the second most prominent cause of death in women. Owing to its intricate nature involving multiple cell types, preventing its onset is challenging. Tyrosine kinase plays a crucial role in cancer development and PTK6, a non-receptor kinase, is recognized as a prognostic biomarker for cancer. Consequently, inhibition of PTK6 has emerged as a potential strategy to curb breast cancer cell proliferation and survival. Dasatinib, an oral SRC-family kinase inhibitor, exhibits robust anti-proliferative, anti-metastatic, and anti-osteoclastic properties, demonstrating sensitivity in triple-negative or basal-like breast cancer cell lines. Materials and Methods: In this context, our study aimed to identify potent lead compounds against breast cancer by leveraging dasatinib derivatives in the pursuit of robust inhibitors. Our methodology encompassed various parameters, including derivative construction by the online tool MolOpt which is freely available and widely used. Further molecular docking, ADME analysis, PASS prediction, rodent toxicity assessment, potential adverse effect evaluation, and MD with PCA calculations were investigated. Results: Through meticulous analysis, we compiled a substantial dataset of 163 derivatives from which the top two compounds compound 1 and compound 10 emerged following rigorous parameter evaluation. Conclusion: After filtration, the identified candidates underwent further scrutiny via MD and PCA analyses which helped to ascertain their potential as promising drug-like substances capable of inhibiting breast cancer effectively. [ABSTRACT FROM AUTHOR]

In the present work, phytoconstituents from Citrus limon are computationally tested against SARS‐CoV‐2 target protein such as Mpro ‐ (5R82.pdb), Spike ‐ (6YZ5.pdb) &RdRp ‐ (7BTF.pdb) for COVID‐19. Docking was done by glide model, QikProp was performed by in silico ADMET screening & Prime MM‐GB/SA modules were used to define binding energy. When compared with approved COVID‐19 drugs such as Remdesivir, Ritonavir, Lopinavir, and Hydroxychloroquine, plant‐based constituents such as Quercetin, Rutoside, Naringin, Eriocitrin, and Hesperidin. bind with significant G‐scores to the active SARS‐CoV‐2 place. The constituents Rutoside and Eriocitrin were studied in each MD simulation in 100 ns against 3 proteins 5R82.pdb, 6YZ5.pdb and 7BTF.pdb.We performed an assay with significant natural compounds from contacts and in silico results (Rutin, Eriocitrin, Naringin, Hesperidin) using 3CL protease assay kit (B.11529 Omicron variant). This kit contained 3CL inhibitor GC376 as Control. The IC50 value of the test compound was found to be Rutin −17.50 μM, Eriocitrin−37.91 μM, Naringin−39.58 μM, Hesperidine−140.20 μM, the standard inhibitory concentration of GC376 was 38.64 μM. The phytoconstituents showed important interactions with SARS‐CoV‐2 targets, and potential modifications could be beneficial for future development. [ABSTRACT FROM AUTHOR]

The aim of the study is to design and synthesize thiazolidinone derivatives having therapeutic potential using PABA as a core component. The characterization of thiazolidinones MS1–MS6 was carried out using different spectroscopic techniques before being subjected to DFT studies to calculate various parameters such as HOMO/LUMO energy gaps and global chemical properties. Thiazolidinones MS1–MS6 were screened to evaluate their in vitro enzyme inhibition potential. In addition to experimental work, theoretical approaches were used as supporting components to design the enzyme inhibitors. In-silico ADMET and docking studies were performed to check the therapeutic properties of thiazolidinone derivatives. The enzyme inhibition potential predicted that MS1–MS6 have potential to inhibit AChE and BChE. The highest activity was depicted by MS4 with a percentage inhibition of 81.7 ± 1.1% against AChE. The molecular dynamic simulation was run for MS4 showing a similar activity on enzyme compared to the standard inhibitor. Both experimental and theoretical assessments suggested the therapeutic importance of the thiazolidinone derivatives MS1–MS6. In-depth studies are ongoing to complete therapeutic probing in terms of toxicity and chemical uses. PABA based Thiazolidinones MS1-MS6 was synthesized according to reported methods. The structural features of the synthesized compounds were investigated using spectral as well as DFT tools. Various parameters such as HOMO/LUMO energy gaps and global chemical properties were computed with DFT. Thiazolidinones MS1-MS6 were screened to evaluate their in vitro enzyme inhibition potential. In-Silico ADMET and docking studies were performed to check the therapeutic properties of thiazolidinone derivatives. The highest activity was depicted by MS4 with a percentage inhibition of 81.7 ± 1.1% against AChE which was further elaborated with molecular dynamic simulation. Both experimental and theoretical assessments suggested the therapeutic importance of the thiazolidinone derivatives. [ABSTRACT FROM AUTHOR]

Viral illnesses frequently cause excessive inflammation in the body, which adds to the severity of symptoms and problems. Understanding and regulating this inflammatory response is critical for successful viral infection management and therapy. It is traditional Ayurvedic understanding to reduce inflammation with formulations of Tulsi, Dalchini, Sunthi, and Krishan mirch. Using computer-aided drug discovery methodologies, this study aims to find phytochemicals that interact with TBK1 and are likely to have this anti-inflammatory effect. Molecular docking results revealed that Oleanolic acid, Astiaticoside A, Cepharadione A, Proanthrocyanidin, and Alpha carotene had binding scores of −8.1 kcal/mol, −7.8 kcal/mol, −6.8 kcal/mol, −6.75 kcal/mol, and −6.8 kcal/mol against TBK1, respectively. 20 ns MD simulations of TBK1 in complex with phytochemicals were performed to evaluate complex stability and protein conformational changes. The simulations showed stable complexes with favourable energy profiles, as evidenced by characteristics such as RMSD, RMSF, Rg, and hydrogen bonding. The MM-PBSA analysis produced precise binding affinity estimates. This work emphasises the potential of these phytochemicals and the need for additional in vitro and in vivo validation. [ABSTRACT FROM AUTHOR]

Graphene films,as a two-dimensional material,are excellent lubricants for improving the tribomechanical properties of micro/nano electro-mechanical systems ( MEMS/NEMS) . In order to investigate the influence of substrate material and graphene layer number on its friction reduction performance,this paper investigates the influence of graphene layer number on the friction reduction effect by preparing graphene coatings with different layer numbers on different substrates and using a combination of atomic force microscopy ( AFM) experiments and molecular dynamics ( MD) simulations. And by establishing the analytical model of the friction performance of graphene coatings with different layer numbers,it was investigated that the interlayer slip of graphene is the main factor to produce the wear reduction. The results show that the graphene coating has excellent wear reduction effect on both silicon substrate and copper substrate under different loads,and the friction decreases gradually with the increase of the number of graphene layers,and reaches the optimal 99. 3% wear reduction effect when the number of graphene layers is more than 10. The simulation analysis reveals that as the number of layers increases,the dry friction between graphene and substrate transforms into interlayer friction of graphene and generates interlayer shear slip,and the interlayer slip of graphene is the main factor leading to the excellent wear reduction performance of multilayer graphene. [ABSTRACT FROM AUTHOR]

L‐cysteine is an essential component in pharmaceutical and agricultural industries, and synthetic biology has made strides in developing new metabolic pathways for its production, particularly in archaea with unique O‐phosphoserine sulfhydrylases (OPSS) as key enzymes. In this study, we employed database mining to identify a highly catalytic activity OPSS from Acetobacterium sp. (AsOPSS). However, it was observed that the enzymatic activity of AsOPSS suffered significant feedback inhibition from the product L‐cysteine, exhibiting an IC50 value of merely 1.2 mM. A semi‐rational design combined with tunnel analysis strategy was conducted to engineer AsOPSS. The best variant, AsOPSSA218R was achieved, totally eliminating product inhibition without sacrificing catalytic efficiency. Molecular docking and molecular dynamic simulations indicated that the binding conformation of AsOPSSA218R with L‐cys was altered, leading to a reduced affinity between L‐cysteine and the active pocket. Tunnel analysis revealed that the AsOPSSA218R variant reshaped the landscape of the tunnel, resulting in the construction of a new tunnel. Furthermore, random acceleration molecular dynamics simulation and umbrella sampling simulation demonstrated that the novel tunnel improved the suitability for product release and effectively separated the interference between the product release and substrate binding processes. Finally, more than 45 mM of L‐cysteine was produced in vitro within 2 h using the AsOPSSA218R variant. Our findings emphasize the potential for relieving feedback inhibition by artificially generating new product release channels, while also laying an enzymatic foundation for efficient L‐cysteine production. [ABSTRACT FROM AUTHOR]

Celiac disease is an autoimmune condition that occurs in genetically susceptible individuals when exposed to gluten, triggering both innate and adaptive immunity. Elevated expression of MAD2L1 in celiac disease makes it a potential target for therapeutic purposes. Phytochemicals are natural compounds found in plants with various health benefits and may play a role in preventing or managing certain diseases. Natural substances block regulatory enzymes that regulate diseases associated with inflammation. In this study, virtual screening from the NPACT small molecule library was conducted to identify therapeutic molecules that could inhibit MAD2L1 activity. Through virtual screening, Ursolic Acid emerged as a candidate with favorable binding properties and interaction characteristics with MAD2L1. The binding affinity of Ursolic Acid with MAD2L1 was determined to be -8.1 kcal/mol. Assessments of ADMET properties and biological function highlighted Ursolic Acid's suitability for further exploration as a therapeutic agent. Molecular docking, MD simulations and MM/GBSA energy calculations demonstrated stable binding of Ursolic Acid with MAD2L1 over 100 ns timeframe. These results suggest promising prospects for developing targeted therapies aimed at modulating MAD2L1 activity and potentially alleviating symptoms associated with celiac disease in genetically susceptible individuals. [ABSTRACT FROM AUTHOR]

The rising antimicrobial resistance crisis has diminished the effectiveness of traditional antibiotics against pathogenic bacteria. This study addresses this urgent challenge by exploring the antibacterial potential of novel quinolone derivatives (1–33). Using computational in silico modeling to simulate biological interactions, we aimed to identify candidates with potent antibacterial activity. A total of 33 quinolone derivatives were assessed for their physicochemical properties and effectiveness against a range of clinically relevant pathogens, including methicillin‐resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Streptococcus pneumoniae, and Enterococcus faecalis. Molecular docking studies identified compounds 28, 29, 32, and 33 as having notable binding affinities, particularly against MRSA. Further molecular dynamics simulations of compound 29 confirmed its favorable stability and potential for disrupting MRSA, reinforcing the docking results and showing strong alignment with in vitro findings. These findings position compound 29 as a promising lead for developing alternative MRSA therapies and underscore the need for further in vivo studies to evaluate its therapeutic potential. [ABSTRACT FROM AUTHOR]

Liver cancer (LC) is one of the most common tumours and the leading cause of cancer‐related death globally. Amidst the problems associated with existing treatments, such as hepatotoxicity, recurrence, drug resistance, and other adverse effects, researchers are under pressure to find alternatives. Towards a comprehensive rationalisation of the search for new anti‐LC drugs among approved ones, we employed an in‐silico approach to accelerate the selection of the most efficacious LC drugs. The FDA‐approved hepatitis C virus (HCV) drugs were docked with the LC protein using the AutoDock Vina software. Compared to the control compound, two FDA‐approved HCV drugs (DB09102 and DB09027) were selected based on their binding energies and interactions with the target protein, which showed comparable binding energies. Furthermore, these compounds were then subjected to molecular dynamic simulation, principle component analysis, and MMGBSA using the AMBER20 software, and the results showed stable complexes compared to the control complex. All things considered, this study will help the scientific community and society find a novel drug to treat LC. [ABSTRACT FROM AUTHOR]

Our research is dedicated to combating HIV by targeting its Matrix (MA) domain, which is crucial for viral assembly and replication. This strategy specifically aims to interrupt early-stage infection and deter drug resistance by focusing on this essential domain. Due to the MA domain's conservation across different HIV strains, our approach promises broad-spectrum efficacy, which is particularly crucial in regions marked by significant genetic diversity and resistance issues. In our study, we introduce CNP0269688, a natural product that exhibits high affinity for the HIV-1 Matrix. Through detailed molecular dynamics simulations, we have assessed the compound's structural stability and interaction dynamics, particularly its potential to hinder Protein-tRNA interactions. This analysis lays the groundwork for future experimental investigations. Our efforts are steps toward enhancing HIV treatment, reducing viral transmission, and curbing drug resistance, with the ultimate aim of controlling and eradicating the pandemic, thereby contributing significantly to public health and scientific advancement. [ABSTRACT FROM AUTHOR]

There is a consensus that epigenomic changes play a significant role in carcinogenesis. The effect of DNA methylation and its increased modulations on gene expression during carcinogenesis is significant for diagnostic and therapeutic purposes. Potential phytochemicals as anticancer approach modulators of epigenetic pathways are the focus of this investigation. Molecular docking studies were conducted to foretell how phytochemicals will interact with DNMT3A. As part of our effort to identify novel anti-cancer treatments, we examined a wide variety of phytochemicals from many chemical classes, including cannabinoids, carotenoids, chalcones, fatty acids, lignans, polysaccharides, saponins, steroids, and tannins. The docking scores for Dihydromyricetin are -10.207 kcal/mol, -9.313 kcal/mol for S-Adenosyl-L-methionine (SAM), and -8.757 kcal/mol for Zeylenol were determined to be superior than to phytochemical inhibitors against DNMT3A in the virtual screening method. Docking scores, hydrogen bond interactions, ADME characteristics, and DFT. Molecular Dynamics Simulation and free energy calculations demonstrated that these compounds bind stably to DNMT3A, potentially inhibiting its activity. Network Pharmacology suggested Dihydromyricetin's specific anticancer potential against cervical cancer. These findings provide insights into protein-Ligand interactions with Dnmt3A and highlights the need for In-vitro validation. [ABSTRACT FROM AUTHOR]

This study involved the synthesis, characterization, and assessment of fourteen pyridazine analogs (designated as 1–14) to investigate their efficacy in inhibiting the α‐amylase enzyme for potential diabetes treatment using an in vitro approach. Additionally, in silico molecular docking and molecular dynamic (MD) simulations were conducted to assess the inhibitory properties of these analogs. Physicochemical and pharmacokinetic properties of the fourteen pyridazine analogs were predicted using the DataWarrior tool. Results indicated that all tested compounds demonstrated significant α‐amylase inhibitory activity, with IC50 values ranging from 81.28±0.00 to 1623.54±2.67 μM compared to the standard drug acarbose (IC50=220.42±36.40 μM). Notably, compounds 8 and 12 exhibited the most potent α‐amylase inhibitory activity, with IC50 values of 81.28±0.00 μM and 200.60±34.65 μM, respectively. Molecular docking analysis revealed binding energies ranging from −7.53 to −5.77 kcal/mol and inhibition constants ranging from 3.00 to 58.96 μM, with compounds 9, 7, 8, 5, and 3 demonstrating the best binding energies. Subsequent MD simulation analyses indicated that all five compound formed stable complexes after 100 ns MD simulation. Consequently, these compounds hold promise as potential α‐amylase inhibitors pending successful clinical validation. [ABSTRACT FROM AUTHOR]

In humans, 15 genes encode the class B1 family of GPCRs, which are polypeptide hormone receptors characterized by having a large N-terminal extracellular domain (ECD) and receive signals from outside the cell to activate cellular response. For example, the insulinotropic polypeptide (GIP) stimulates the glucose-dependent insulinotropic polypeptide receptor (GIPR), while the glucagon receptor (GCGR) responds to glucagon by increasing blood glucose levels and promoting the breakdown of liver glycogen to induce the production of insulin. The glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) elicit a response from glucagon-like peptide receptor types 1 and 2 (GLP1R and GLP2R), respectively. Since these receptors are implicated in the pathogenesis of diabetes, studying their activation is crucial for the development of effective therapies for the condition. With more structural information being revealed by experimental methods such as X-ray crystallography, cryo-EM, and NMR, the activation mechanism of class B1 GPCRs becomes unraveled. The available crystal and cryo-EM structures reveal that class B1 GPCRs follow a two-step model for peptide binding and receptor activation. The regions close to the C-termini of hormones interact with the N-terminal ECD of the receptor while the regions close to the N-terminus of the peptide interact with the TM domain and transmit signals. This review highlights the structural details of class B1 GPCRs and their conformational changes following activation. The roles of MD simulation in characterizing those conformational changes are briefly discussed, providing insights into the potential structural exploration for future ligand designs. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative disorders (NDs), primarily affecting the elderly, are marked by complex pathophysiological processes and are projected to become the second leading cause of death. Parkinson's disease (PD), one of the most common NDs, is characterized by motor impairments due to reduced dopamine levels in the substantia nigra (SN), a crucial midbrain region involved in motor control and reward mechanisms. PD also impacts cognitive functions, potentially leading to depression and sleep disturbances. Recent research highlights the importance of MAO-B inhibitors in PD management, as these enzymes play a critical role in regulating neurotransmitter levels by catalyzing the oxidative deamination of intracellular amines and monoamine neurotransmitters. Result: Computational virtual screening of several quinoline-based ligands against the target protein MAO-B (PDB ID: 1OJA) was performed using molecular docking simulation and ADMET studies to identify promising inhibitors for neurodegenerative disease treatment. The most active hit, Compound PA001, exhibited a MolDock score of − 207.76 kcal/mol. Subsequent investigation of 6-methoxy-2-(4-phenylpiperazin-1-yl)quinoline (Compound PA001) using molecular dynamics (MD) simulations with GROMACS revealed potent inhibition and significant interactions at key active site residues. MD simulations confirmed the stability of the Compound PA001-MAO-B complex under physiological conditions. Additionally, ADMET analysis demonstrated that Compound PA001 possesses favorable drug-like properties, including absorption, distribution, metabolism, excretion, and toxicity profiles. These findings underscore 6-methoxy-2-(4-phenylpiperazin-1-yl)quinoline (Compound PA001) as a promising candidate for developing new MAO-B inhibitors to treat neurodegenerative diseases. Conclusion: The research highlighted 6-methoxy-2-(4-phenylpiperazin-1-yl)quinoline (Compound PA001) as a promising MAO-B inhibitor, exhibiting strong binding affinity, stability, and desirable drug-like characteristics for the treatment of neurodegenerative diseases. Among the top ten molecules, Compound PA001 was selected for molecular dynamics (MD) simulation using GROMACS. The compound showed potent inhibition, significant interactions with key active site residues, and stable complex formation under physiological conditions. ADMET analysis further confirmed its favorable pharmacokinetic profile. [ABSTRACT FROM AUTHOR]

Cathepsin K (CatK), a lysosomal cysteine protease, contributes to skeletal abnormalities, heart diseases, lung inflammation, and central nervous system and immune disorders. Currently, CatK inhibitors are associated with severe adverse effects, therefore limiting their clinical utility. This study focuses on exploring quantitative structure–activity relationships (QSAR) on a dataset of CatK inhibitors (1804) compiled from the ChEMBL database to predict the inhibitory activities. After data cleaning and pre-processing, a total of 1568 structures were selected for exploratory data analysis which revealed physicochemical properties, distributions and statistical significance between the two groups of inhibitors. PubChem fingerprinting with 11 different machine-learning classification models was computed. The comparative analysis showed the ET model performed well with accuracy values for the training set (0.999), cross-validation (0.970) and test set (0.977) in line with OECD guidelines. Moreover, to gain structural insights on the origin of CatK inhibition, 15 diverse molecules were selected for molecular docking. The CatK inhibitors (1 and 2) exhibited strong binding energies of −8.3 and −7.2 kcal/mol, respectively. MD simulation (300 ns) showed strong structural stability, flexibility and interactions in selected complexes. This synergy between QSAR, docking, MD simulation and machine learning models strengthen our evidence for developing novel and resilient CatK inhibitors. [ABSTRACT FROM AUTHOR]

Background: Staphylococcal scalded skin syndrome (SSSS) is a dermatological condition caused by Staphylococcus aureus, characterized by exfoliative toxin B, and its increasing resistance to conventional antibiotics necessitates the search for new therapeutic options. Aim: The study aimed to investigate the potential of traditional medicinal compounds (TMCs) as potential pharmaceuticals against SSSS using molecular-level research. Introduction: Staphylococcus aureus, commonly known as S. aureus, is the main cause of SSSS. These infections are a major concern for public health because they are becoming resistant to antibiotics. There is an urgent need for new medications to effectively fight against this infection. The main objective of this study was to assess the interaction between TMC compounds and S. aureus exfoliative toxins ETA and ETB utilizing computational approaches. Materials and Methods: The investigation selected TMC compounds based on their potential to combat S. aureus infections. To predict binding affinities with the ETB toxin, molecular docking simulations were performed using AutoDock and AutoDock Vina. In order to evaluate the stability and interaction dynamics with the toxins, the most promising compound was subjected to a 100 ns molecular dynamics simulation. Stability was evaluated through various methods. Results: Liquiritin showed the highest binding affinity, with a docking score of −7.6 kcal/mol. MD simulation confirmed the complex's stability, and the binding free energy of −17.76 kcal/mol indicated potent inhibitory activity against S. aureus ETB. Conclusion: Liquiritin, a TMC, effectively inhibits S. aureus toxins ETB, with promising potential for treating SSSS and antibiotic-resistant infections, requiring further research. [ABSTRACT FROM AUTHOR]

Outbreaks of Monkeypox (mpox) in over 100 non-endemic countries in 2022 represented a serious global health concern. Once a neglected disease, mpox has become a global public health issue. A42R profilin-like protein from mpox (PDB ID: 4QWO) represents a potential new lead for drug development and may interact with various synthetic and natural compounds. In this report, the interaction of A42R profilin-like protein with six phytochemicals found in the medicinal plant Ficus religiosa (abundant in India) was examined. Based on the predicted and compared protein–ligand binding energies, biological properties, IC50 values and toxicity, two compounds, kaempferol (C-1) and piperine (C-4), were selected. ADMET characteristics and quantitative structure–activity relationship (QSAR) of these two compounds were determined, and molecular dynamics (MD) simulations were performed. In silico examination of the kaempferol (C-1) and piperine (C-4) interactions with A42R profilin-like protein gave best-pose ligand-binding energies of –6.98 and –5.57 kcal/mol, respectively. The predicted IC50 of C-1 was 7.63 μM and 82 μM for C-4. Toxicity data indicated that kaempferol and piperine are non-mutagenic, and the QSAR data revealed that piperlongumine (5.92) and piperine (5.25) had higher log P values than the other compounds examined. MD simulations of A42R profilin-like protein in complex with C-1 and C-4 were performed to examine the stability of the ligand–protein interactions. As/C and C-4 showed the highest affinity and activities, they may be suitable lead candidates for developing mpox therapeutic drugs. This study should facilitate discovering and synthesizing innovative therapeutics to address other infectious diseases. [ABSTRACT FROM AUTHOR]

Context: This work introduces a method for generating generalized structures of amorphous polymers using simulated polymerization and molecular dynamics equilibration, with a particular focus on amorphous polymers. The techniques and algorithms used in this method are described in the main text, and example input scripts are provided for the GMXPolymer code, which is based on the GROMACS molecular dynamics package. To demonstrate the efficacy of our method, we apply it to different glassy polymers exhibiting varying degrees of functionality, polarity, and rigidity. The reliability of the method is validated by comparing simulation results with experimental data in various structural and thermal properties, both of which show excellent agreement. Methods: This work implements the GMXPolymer simulated polymerization algorithm on the GROMACS program. GMXPolymer code controls the main polymerization loop. The energy minimizations and molecular dynamics simulations use the GROMACS program called by the GMXPolymer code. A new ITP file is generated when a new bond is formed, and the necessary additions to the ITP file are made to include new bonds, angles, and dihedrals. In preparing the ITP file of the monomer, the charge of the reactive atom must be modified before the code runs so that it is a correct value after bonding. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus infections present a significant threat to the global healthcare system. The increasing resistance to existing antibiotics and their limited efficacy underscores the urgent need to identify new antibacterial agents with low toxicity to effectively combat various S. aureus infections. Hence, in this study, we have screened T-muurolol for possible interactions with several S. aureus-specific bacterial proteins to establish its potential as an alternative antibacterial agent. Based on its binding affinity and interactions with amino acids, T-muurolol was identified as a potential inhibitor of S. aureus lipase, dihydrofolate reductase, penicillin-binding protein 2a, D-Ala:D-Ala ligase, and ribosome protection proteins tetracycline resistance determinant (RPP TetM), which indicates its potentiality against S. aureus and its multi-drug-resistant strains. Also, T-muurolol exhibited good antioxidant and anti-inflammatory activity by showing strong binding interactions with flavin adenine dinucleotide (FAD)-dependent nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, and cyclooxygenase-2. Consequently, molecular dynamics (MD) simulation and recalculating binding free energies elucidated its binding interaction stability with targeted proteins. Furthermore, quantum chemical structure analysis based on density functional theory (DFT) depicted a higher energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital (EHOMO-LUMO) with a lower chemical potential index, and moderate electrophilicity suggests its chemical hardness and stability and less polarizability and reactivity. Additionally, pharmacological parameters based on ADMET, Lipinski's rules, and bioactivity score validated it as a promising drug candidate with high activity toward ion channel modulators, nuclear receptor ligands, and enzyme inhibitors. In conclusion, the current findings suggest T-muurolol as a promising alternative antibacterial agent that might be a potential phytochemical-based drug against S. aureus. This study also suggests further clinical research before human application. [ABSTRACT FROM AUTHOR]

Understanding how supercoiled DNA releases intramolecular stress is essential for its functional realization. However, the molecular mechanism underlying the relaxation process remains insufficiently explored. Here we employed MD simulations based on the oxDNA2 model to investigate the relaxation process of a 336-base pair supercoiled minicircular DNA under double-strand breaks with two fixed endpoints. Our simulations show that the conformational changes in the DNA occur continuously, with intramolecular stress release happening abruptly only when the DNA chain traverses the breakage site. The relaxation process is influenced not only by the separation distance between the fixed ends but also their angle. Importantly, we observe an inhibitory effect on the relaxation characterized by small angles, where short terminal loops impede DNA conformational adjustments, preserving the supercoiled structure. These findings elucidate the intricate interplay between DNA conformational change, DNA motion and intramolecular stress release, shedding light on the mechanisms governing the relaxation of supercoiled DNA at the molecular level. [ABSTRACT FROM AUTHOR]

This paper conducts a computational investigation of the phase behaviour of $ \textrm{C}{\textrm{H}_4} $ C H 4 - $ \textrm{C}{\textrm{O}_2} $ C O 2 binary system, utilising the SAFT-VR Mie equation of state alongside molecular dynamics (MD) simulations. Molecular parameters for pure $ \textrm{C}{\textrm{H}_4} $ C H 4 and $ \textrm{C}{\textrm{O}_2} $ C O 2 compounds were obtained by fitting the SAFT-VR Mie EOS to vapour pressure and saturated liquid density experimental data. The research first validates the SAFT-VR Mie EOS on thermodynamic properties and vapour–liquid equilibria for different compositions, pressures, and temperatures of pure $ \textrm{C}{\textrm{H}_4} $ C H 4 , $ \textrm{C}{\textrm{O}_2} $ C O 2 , and $ \textrm{C}{\textrm{H}_4} $ C H 4 - $ \textrm{C}{\textrm{O}_2} $ C O 2 mixtures with the newly extracted parameters. The study confirms the EOS's accurate prediction of coexistence properties, including pressure, density, and phase-equilibrium curve. MD simulations were performed using the LAMMPS software package, with Mie force field parameters derived from this study for non-bonded interactions. Simulations were conducted using three other force fields (OPLS-UA, UFF, and GAFF) to compare their performance with our approach. The simulation results were compared to laboratory data, or REFPROP, in the absence of laboratory data. The results showed a relatively good agreement, indicating that combining SAFT-VR Mie EOS and MD simulations is a reliable predictive tool for designing gas processing and gas storage applications involving $ \textrm{C}{\textrm{H}_4} $ C H 4 - $ \textrm{C}{\textrm{O}_2} $ C O 2 mixtures. This approach also mitigates the need for expensive and hazardous high-pressure laboratory techniques. [ABSTRACT FROM AUTHOR]

BACKGROUND: Carboxypeptidase is an exopeptidase that hydrolyzes amino acids at the C‐terminal end of the peptide chain and has a wide range of applications in food. However, in industrial applications, the relatively low catalytic efficiency of carboxypeptidases is one of the main limiting factors for industrialization. RESULTS: The study has enhanced the catalytic efficiency of Bacillus megaterium M32 carboxypeptidase (BmeCPM32) through semi‐rational design. Firstly, the specific activity of the optimal mutant, BmeCPM32‐M2, obtained through single‐site mutagenesis and combinatorial mutagenesis, was 2.2‐fold higher than that of the wild type (187.9 versus 417.8 U mg−1), and the catalytic efficiency was 2.9‐fold higher (110.14 versus 325.75 s−1 mmol−1). Secondly, compared to the wild type, BmeCPM32‐M2 exhibited a 1.8‐fold increase in half‐life at 60 °C, with no significant changes in its enzymatic properties (optimal pH, optimal temperature). Finally, BmeCPM32‐M2 significantly increased the umami intensity of soy protein isolate hydrolysate by 55% and reduced bitterness by 83%, indicating its potential in developing tasty protein components. CONCLUSION: Our research has revealed that the strategy based on protein sequence evolution and computational residue mutation energy led to an improved catalytic efficiency of BmeCPM32. Molecular dynamics simulations have revealed that a smaller substrate binding pocket and increased enzyme–substrate affinity are the reasons for the enhanced catalytic efficiency. Furthermore the number of hydrogen bonds and solvent and surface area may contribute to the improvement of thermostability. Finally, the de‐bittering effect of BmeCPM32‐M2 in soy protein isolate hydrolysate suggests its potential in developing palatable protein components. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Transition metal dichalcogenides (TMDCs) are among the most exciting materials in nano-size particles. In this study, MX2 (M = Mo and W; X = S, Se, and Te) nanotubes and monolayers were evaluated to show the structural, mechanical, and electronic properties. The results showed that the stability of MX2 monolayers changes similarly to nanotubes with the sequence of MS2 > MSe2 > MTe2 (M = Mo and W). Besides, MX2 nanotubes and monolayers are semiconductors, and the band gap energy increases with a similar sequence with stability properties. The structural stability and band gap energy of WX2 structures are more than MoX2 structures. Young's modulus of nanotubes was studied with density functional theory (DFT) and molecular dynamics (MD) simulations with Stillinger-Weber (SW) potential methods. The results are similar to the formation and band gap energy showing that Young's modulus of the MX2 structures is in order of MS2 > MSe2 > MTe2 (M = Mo and W) and WX2 > MoX2 (X = S, Se or Te). Structural defects in monolayers, which were M-vacancy (VM), X2-vacancy (VX2), M-X2-vacancy (VM-X2), and M-X4-vacancy (VM-X4), were studied and it showed that the mechanical properties could be decreased. However, the defects do not affect electronic properties. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations have been employed to investigate the transformation of structural units at the grain boundary under tensile conditions. A series of symmetric tilt-[110]-Σ27 bi-crystal Cu models are considered in this research. The findings indicate that atomic potential energy significantly influences the transformation of structural units. The potential energy of the common atom from two neighbouring structural units breaks through the threshold due to external loading, leading to its migration to adjacent atomic layers. This migration triggers the transformation of the structural unit and results in the nucleation of dislocations on the grain boundaries, which further leads to a precipitous decline in the potential energy of the grain boundaries. [ABSTRACT FROM AUTHOR]

At present, there are few studies on the phase transition during the thermocompression plastic deformation of magnesium alloy. In this study, the evolution model of thermal compression plastic of AZ31 magnesium alloy was constructed by molecular dynamics, and the phase transition relationship between HCP and FCC at different thermal compression rates was studied. By combining GLEEBLE thermal compression experiment with transmission electron microscopy experiment, high-resolution transmission electron microscopy images were taken to analyze the transition rules between HCP and FCC during plastic deformation at different thermal compression rates, and the accuracy of molecular dynamics analysis was verified. It is found that the slip of Shockley's incomplete dislocation produces obvious HCP →FCC phase transition at low strain rate and base plane dislocation at high strain rate, which makes the amorphous phase transition of HCP→OTHER more obvious, which provides theoretical guidance for the formulation of forming mechanism and preparation process of magnesium alloy. [ABSTRACT FROM AUTHOR]

Epithelial Ovarian Cancer (EOC) presents a global health concern, necessitating the development of innovative therapeutic strategies to combat its impact. This study was employed to investigate the unexplored therapeutic efficacy of Cynodon dactylon phytochemicals against EOC using a multifaceted computational approach. A total of 19 out of 89 rigorously curated phytochemicals were assessed as potential drug targets via ADMET profiling, while protein-protein interaction analysis scrutinized the top 20 hub genes among 264 disease targets, revealing their involvement in cancer-related pathways and underscoring their significance in EOC pathogenesis. In molecular docking, Stigmasterol acetate showed the highest binding affinity (−10.9 kcal/mol) with Poly [ADP-ribose] polymerase-1 (PDB: 1UK1), while Arundoin and Beta-Sitosterol exhibited strong affinities (−10.4 kcal/mol and −10.1 kcal/mol, respectively); additionally, Beta-Sitosterol interacting with Mitogen-activated protein kinase 3 (PDB: 4QTB) showed a binding affinity of −10.1 kcal/mol, forming 2 hydrogen bonds and a total of 10 bonds with 10 residues. Molecular dynamics simulations exhibited the significant structural stability of the Beta-Sitosterol-4QTB complex with superior binding free energy (−36.61 kcal/mol) among the three complexes. This study identified C. dactylon phytosterols, particularly Beta-Sitosterol, as effective in targeting MAPK3 and PARP1 to combat EOC, laying the groundwork for further experimental validation and drug development efforts. [ABSTRACT FROM AUTHOR]

Cervical Cancer remains a women's health concern worldwide and ranks among the most prevalent cancers, particularly in developing countries. Many women are diagnosed with cervical cancer, with a substantial number succumbing to the disease even after the availability of vaccines and drugs. The tumour microenvironment often exhibits immune evasion, including suppression of T-cell activity and altered cytokine, impacting the efficacy of therapeutic interventions and highlighting the need for treatments to modulate the immune response. Despite efforts to promote HPV vaccination and regular screenings, it causes many deaths, underscoring the urgent need for continued research, healthcare access, and rapid drug development or repurposing. In this study, we identified various proteins involved in cervical cancer cell cycle regulation and DNA replication proteins, performed the multitargeted docking with an FDA-approved library, and identified Oxidopamine HBr as a multitargeted drug. Studies extended with pharmacokinetics and compared with the standard values followed by DFT, which supported the compound as a multitargeted inhibitor. Further, the docked complexes were taken for the interaction fingerprints, and it was identified that there are many 9 polar, 5 hydrophobic, 2 aromatic, and 2 basic residues. We extended our studies for 100ns MD Simulation in water, and the computations explored the deviation and fluctuations under 2Å and many intermolecular interactions; the same trajectory files were used for the MM\GBSA studies. All the studies have supported the Oxidopamine HBr as a cervical cancer multitargeted inhibitor—however, experimental studies are needed before human use. [ABSTRACT FROM AUTHOR]