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Muhammad Faheem,1 Yusuf S Althobaiti,2,3 Abdul Waheed Khan,4 Aman Ullah,1 Syed Hussain Ali,1 Umair Ilyas1 1Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan; 2Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, Taif, 21944, Saudi Arabia; 3Addiction and Neuroscience Research Unit, Taif University, Taif, 21944, Saudi Arabia; 4Department of Pharmacy, The University of Lahore, Islamabad, PakistanCorrespondence: Muhammad Faheem; Yusuf S Althobaiti Email muhammad.faheem@riphah.edu.pk; althobaiti@tu.edu.saObjective: The study investigated the effect 5-[(naphthalen-2-yloxy) methyl]-1,3,4-oxadiaszole2-thiol (B3) in animal model of acute epileptic shock.Methods: The pharmacokinetics profile of B3 was checked through SwissADME software. The binding affinities of B3, diazepam, and flumazenil (FLZ) were obtained through Auto Dock and PyRx. Post docking analysis and interpretation of hydrogen bonds were performed through Discovery Studio Visualizer 2016. Molecular dynamics simulations of three complexes were carried out through Desmond software package. B3 was then proceeded in PTZ-induced acute seizures models. Flumazenil was used in animal studies for elucidation of possible mechanism of B3. After behavioral studies, the animals were sacrificed, and the brain samples were isolated and stored in 4% formalin for molecular investigations including H and E staining, IHC staining and Elisa etc.Results: The results demonstrate that B3 at 20 and 40 mg/kg prolonged the onset time of generalized seizures. B3 considerably increased the expression of protective glutathione S-transferase and glutathione reductase and reduced lipid peroxidation and inducible nitric oxide synthase (P < 0.001) in the cortex. B3 significantly suppressed (P < 0.01) the over expression of the inflammatory mediator tumor necrosis factor–α, whose up-regulation is reported in acute epileptic shocks.Conclusion: Hence, it is concluded from the aforementioned results that B3 provides neuroprotective effects PTZ-induced acute epileptic model. FLZ pretreatment resulted in inhibition of the anticonvulsant effect of B3. B3 possesses anticonvulsant effect which may be mediated through GABAA mediated antiepileptic pathway.Keywords: docking, molecular dynamic simulations, gamma amino butyric acid A

This work investigated the adsorption mechanism of heavy metals: silver (Ag), mercury (Hg), cadmium (Cd), palladium (Pd), and zinc (Zn) on the carbon graphite (111) surface based on density functional theory (DFT), Metropolis Monte Carlo (MMC), and the molecular dynamics (MD) simulation methods. The obtained results from the adsorption of these species showed that the process is spontaneous and exothermic in nature. The maximum adsorption capacities were obtained in neutral to low acid medium, and the interaction between Hg-carbon graphite was more favored than other systems. These findings showed that carbon graphite was more efficient in the removal of the studied metals. Moreover, this study better explains the adsorption mechanism of heavy metals onto carbon graphite and gives a theoretical basis for the wider application of graphite adsorbent in the removal of heavy metals. This paper provides theoretical support for heavy metals removal in various mediums and also provides some new ideas for the secondary utilization of quantum chemical descriptors and molecular dynamics simulation methods.

In this study we aim to investigate the computational docking approach of biofabricated silver nanoparticles against P. aeruginosa virulent exoenzymes, such as ExoS and ExoY. Therefore, the synthesis and characterization of biofabricated silver nanoparticles using Piper betle leaves (Pb-AgNPs) were carried out. The surface topology and functional group attachment on the surface of Pb-AgNPs were analyzed using UV–visible spectroscopy, Scanning Electron Microscopy, Fourier Transformed Infrared Spectroscopy (FTIR), and X-Ray Diffraction. The FTIR analysis revealed that the synthesized silver nanoparticles were capped with P. betle phytochemicals importantly Eugenol and Hydroxychavicol. These are the major bioactive compounds present in P. betle leaves; therefore, computational docking of Eugenol-conjugated AgNPs (PbEu-AgNPs) and Hydroxychavicol-conjugated AgNPs (PbHy-AgNPs) against ExoS and ExoY was performed. The active residues of PbEu-AgNPs and PbHy-AgNPs interacted with the active site of ExoS and ExoY exoenzymes. Biofabricated AgNP-mediated inhibition of these virulent exoenzymes blocked the adverse effect of P. aeruginosa on the host cell. The computational analysis provides new approach into the design of biofabricated AgNPs as promising anti-infective nanomedicine agents. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes are a virulence factor in many Gram-positive organisms. The specific activity of the Bacillus thuringiensis PI-PLC is significantly increased by adding phosphatidylcholine (PC) to vesicles composed of the substrate phosphatidylinositol, in part because the inclusion of PC reduces the apparent Kd for the vesicle binding by as much as 1000-fold when comparing PC-rich vesicles to PI vesicles. This review summarizes (i) the experimental work that localized a site on BtPI-PLC where PC is bound as a PC choline cation—Tyr-π complex and (ii) the computational work (including all-atom molecular dynamics simulations) that refined the original complex and found a second persistent PC cation—Tyr-π complex. Both complexes are critical for vesicle binding. These results have led to a model for PC functioning as an allosteric effector of the enzyme by altering the protein dynamics and stabilizing an 'open' active site conformation. [ABSTRACT FROM AUTHOR]

Evodiamine (EVO) and rutaecarpine (RUT) are the main active compounds of the traditional Chinese medicinal herb Evodia rutaecarpa. Here, we fully optimized the molecular geometries of EVO and RUT at the B3LYP/6-311++G (d, p) level of density functional theory. The natural population analysis (NPA) charges, frontier molecular orbitals, molecular electrostatic potentials, and the chemical reactivity descriptors for EVO and RUT were also investigated. Furthermore, molecular docking, molecular dynamics simulations, and the analysis of the binding free energies of EVO and RUT were carried out against the anticancer target topoisomerase 1 (TOP1) to clarify their anticancer mechanisms. The docking results indicated that they could inhibit TOP1 by intercalating into the cleaved DNA-binding site to form a TOP1–DNA–ligand ternary complex, suggesting that they may be potential TOP1 inhibitors. Molecular dynamics (MD) simulations evaluated the binding stability of the TOP1–DNA–ligand ternary complex. The calculation of binding free energy showed that the binding ability of EVO with TOP1 was stronger than that of RUT. These results elucidated the structure–activity relationship and the antitumor mechanism of EVO and RUT at the molecular level. It is suggested that EVO and RUT may be potential compounds for the development of new anticancer drugs. [ABSTRACT FROM AUTHOR]

Aim and Background: Mycobacterium tuberculosis (TB) remains the leading cause of human death posing one of the most serious threats to public health around the world. New strategies need to be developed to combat the growing danger by multidrug resistance. The present study aims to screen three different compounds inhibiting the binding pocket of Regulatory Repressor Protein EthR of Mycobacterium tuberculosis. In this study we performed pharmacophore modeling based virtual screening to identify the potential inhibitors against EthR of Mycobacterium tuberculosis. Based on the binding energy and hydrogen bond interactions three compounds were selected as potential inhibitors. Materials and Methods: Structure of EthR protein (PDB ID: 5NZ0) was retrieved from pdb databank. Further, we retrieved ligands from ZINC database (ZINC223412753, ZINC030691754, ZINC170602403). Next, Computational screening, Docking studies and Molecular dynamic simulations were performed to validate the stability of the complexes. Results: The molecular docking showed that all ligands interact with EthR protein of Mycobacteriam. Further, molecular dynamics simulation showed that ligand ZINC223412753 form comparatively more stable complex with EthR. Results showed that all the three ligands could be a potential inhibitor of EthR. Conclusion: These compounds can serve as a starting point in rational design of selective potent inhibitors against Mycobacterium tuberculosis. [ABSTRACT FROM AUTHOR]

Mycoplasma genitalium, besides urethritis, causes a number of other sexually transmitted diseases, posing a significant health threat to both men and women, particularly in developing countries. In light of the rapid appearance of multidrug-resistant strains, M. genitalium is regarded as an emerging threat and has been placed on the CDC's "watch list". Hence, a protective vaccine is essential for combating this pathogen. In this study, we utilized reverse vaccinology to develop a chimeric vaccine against M. genitalium by identifying vaccine targets from the reference proteome (Strain G-37) of this pathogen. A multiepitope vaccine was developed using proteins that are non-toxic, non-allergic, and non-homologous to human proteins. Several bioinformatic tools identified linear and non-linear B-cell epitopes, as well as MHC epitopes belonging to classes I and II, from the putative vaccine target proteins. The epitopes that showed promiscuity among the various servers were shortlisted and subsequently selected for further investigation based on an immunoinformatic analysis. Using GPGPG, AAY, and KK linkers, the shortlisted epitope sequences were assembled to create a chimeric construct. A GPI anchor protein immunomodulating adjuvant was adjoined to the vaccine construct's N-terminus through the EAAK linker so as to improve the overall immunogenicity. For further investigations of the designed construct, various bioinformatic tools were employed to study the physicochemical properties, immune profile, solubility, and allergenicity profile. A tertiary chimeric design was computationally modeled using I-TASSER and Robetta and was subsequently refined through GalaxyRefine. ProSA-Web was exploited to corroborate the quality of the construct by detecting errors and the Ramachandran plot was used to identify possible quality issues. Simulation studies of the molecular dynamics demonstrated the robustness and flexibility of the designed construct. Following the successful docking of the designed model to the immune receptors, the construct was computationally cloned into Escherichia coli plasmids to affirm the efficient expression of the designed construct in a biological system. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using a combination of drug repositioning and rigorous computational modeling methodologies such as molecular docking and molecular dynamics (MD) simulations followed by binding free energy calculations. Six FDA-approved drugs including, Ouabain, Digitoxin, Digoxin, Proscillaridin, Salinomycin and Niclosamide with promising anti-SARS-CoV-2 activity were screened in silico against four SARS-CoV-2 proteins—papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), SARS-CoV-2 main protease (Mpro), and adaptor-associated kinase 1 (AAK1)—in an attempt to define their promising targets. The applied computational techniques suggest that all the tested drugs exhibited excellent binding patterns with higher scores and stable complexes compared to the native protein cocrystallized inhibitors. Ouabain was suggested to act as a dual inhibitor for both PLpro and Mpro enzymes, while Digitoxin bonded perfectly to RdRp. In addition, Salinomycin targeted PLpro. Particularly, Niclosamide was found to target AAK1 with greater affinity compared to the reference drug. Our study provides comprehensive molecular-level insights for identifying or designing novel anti-COVID-19 drugs. [ABSTRACT FROM AUTHOR]

Globally, cancer is the second leading cause of mortality and morbidity. The growth and development of cancer are extremely complex. It is caused by a variety of pathways and involves various types of enzymes. Pyruvate kinase M2 (PKM2) is an isoform of pyruvate kinase, that catalyses the last steps of glycolysis to produce energy. PKM2 is relatively more expressed in tumour cells where it tends to exist in a dimer form. Various medicinal plants are available that contain a variety of micronutrients to combat against different cancers. The phytocompounds of the olive tree (Olea europaea) leaves play an important role in inhibiting the proliferation of several cancers. In this study, the phytocompounds of olive leaf extract (OLE) were studied using various in silico tools, such as pkCSM software to predict ADMET properties and PASS Online software to predict anticancer activity. However, the molecular docking study provided the binding energies and inhibition constant and confirmed the interaction between PKM2 and the ligands. The dynamic behaviour, conformational changes, and stability between PKM2 and the top three hit compounds (Verbascoside (Ver), Rutin (Rut), and Luteolin_7_O_glucoside (Lut)) are studied by MD simulations. [ABSTRACT FROM AUTHOR]

Nicotinamide is a high‐value chemical that has been widely applied in various aspects of daily life. Nitrile hydratase (NHase) is capable of carrying out biotransformation of nitriles to amides and has shown great potential in the green synthesis of nicotinamide. The high‐molecular mass NHase (H‐NHase) from Rhodococcus rhodochrous J1 has been applied in the industrial‐scale production of acrylamide; however, its activity is not ideal towards aromatic 3‐cyanopyridines, resulting in its substrate preference towards aliphatic nitriles. In this study, a hinge residue at the entrance of the substrate access tunnel of H‐NHase was identified through substrate access tunnel calculations, site‐saturation mutagenesis, molecular docking and molecular dynamics simulations. The corresponding mutant βW48Y showed a 5.9‐fold higher specific activity towards 3‐cyanopyridine than that of its parental enzyme, with better thermostability, proving itself to be a competitive candidate for the industrial production of nicotinamide. [ABSTRACT FROM AUTHOR]

Allosteric kinase inhibitors targets kinases with oncogenic driver mutations in malignancies as a potential new therapy strategy. EGFR inhibitors with a 4-oxo-chromane scaffold targeting the L858R/T790M/C797S mutation were identified, optimized, synthesized, and assessed for anticancer and EGFR enzyme inhibitory activity. Compounds 4i and 4l were shown to be very effective with IC50 values of 132 and 146 nM, respectively, and excellent selectivity in in silico study. Compound 4i showed substantial antioxidant activity at a concentration of 100 µM, with a DPPH radical scavenging value of 91.46%. The synthesized compounds 4i, 4k and 4l were found to be selective toward cancer cells since they did not exhibit cytotoxicity even at IC50 > 20 µM on normal cells. Compound potency was further assessed using in silico and in vitro biological evaluation. [ABSTRACT FROM AUTHOR]

This research investigates antiviral potential of extracted honeybee products against COVID-19 main protease (Mpro) by computational methods. The crystal structure of COVID-19 Mpro was obtained from the protein data bank. Six synthetic drugs with antiviral properties were used as control samples in order to compare the results with those of natural ligands. The six honeybee components, namely 3,4,5-Tricaffeoylquinic acid, Kaempferol-3-O-glucoside, (E)-2′-Geranyl-3′,4′,7-Trihydroxyflavanone, 6-Cinnamylchrysin, (+)-Pinoresinol, and (24E)-3-Oxo-27,28-dihydroxycycloart-24-en-26-oic acid, have represented the lowest binding energies of −9.0, −8.5, −8.2, −7.8, −7.7, −7.3 and −6.7 Kcal/mol, respectively. These natural inhibitors were then picked for further investigations on their pharmacokinetic features. Also a 150 ns of Molecular dynamics simulations were carried out in order to evaluate their effects on protein structure and dynamics. The 3, 4, 5-Tricaffeoylquinic acid is hopefully proposed for COVID-19 Mpro inhibition if further in vitro, in vivo, and clinical trial studies will approve its effectiveness against COVID-19. [ABSTRACT FROM AUTHOR]

Exploration and development of cost‐effective, ultra‐long durability, and high‐performing non‐noble‐metal catalysts for the oxygen reduction reaction (ORR) to replace Pt‐based catalysts for electrochemical energy conversion devices is still of great challenge. Although several types of non‐noble‐metal catalysts (N‐doped graphene, transition metal nanoparticles, single atomic metal‐nitrogen‐carbon, etc.) are claimed to have comparable or overwhelming catalytic performances compared with commercial Pt/C, their long‐durability, especially in harsh electrolytes, are still unsatisfactory for practical applications. Herein, the classical Fe3C‐NG catalysts are synthesized and investigated to understand the catalytic and degradation behaviors in Zn‐Air batteries. Experimental analysis and theoretical calculations reveal that the Mott–Schottky heterojunction formed by Fe3C quantum dots (QDs) and N‐doped graphene carbon (Fe3C‐NG) boosts the ORR, since the Fe3C quantum dots provide rapid electron transfer to the valence band of NG. Molecular dynamic simulation suggests that the graphene structure in NG is relatively stable in extremely corrosive electrolyte, which avoids the corrosion of Fe3C quantum dots. In combination of the Zn/graphene composite film and solid‐state electrolyte, the optimized Zn‐air battery with Fe3C‐NG catalyst delivers a high open circuit voltage of 1.506 V, high energy density of 706.4 Wh kg–1, and long‐term stability for 1000 h. [ABSTRACT FROM AUTHOR]

2C is a highly conserved picornaviral non-structural protein with ATPase activity and plays a multifunctional role in the viral life cycle as a promising target for anti-picornavirus drug development. While the structure-function of enteroviral 2Cs have been well studied, cardioviral 2Cs remain largely uncharacterized. Here, an endogenous ATP molecule was identified in the crystal structure of 2C from encephalomyocarditis virus (EMCV, Cardiovirus A). The ATP is bound into the ATPase active site with a unique compact conformation. Notably, the γ-phosphate of ATP directly interacts with Arg311 (conserved in cardioviral 2Cs), and its mutation significantly inhibits the ATPase activity. Unexpectedly, this mutation remarkably promotes 2C self-oligomerization and viral replication efficiency. Molecular dynamic simulations showed that the Arg311 side chain is highly dynamic, indicating it may function as a switch between the activation state and the inhibition state of ATPase activity. A hexameric ring model of EMCV 2C full length indicated that the C-terminal helix may get close to the N-terminal amphipathic helices to form a continuous positive region for RNA binding. The RNA-binding studies of EMCV 2C revealed that the RNA length is closely associated with the RNA-binding affinities and indicated that the substrate may wrap around the outer surface of the hexamer. Our studies provide a biochemical framework to guide the characterization of EMCV 2C and the essential role of arginine in cardioviral 2C functions., Importance: Encephalomyocarditis virus (Cardiovirus A) is the causative agent of the homonymous disease, which may induce myocarditis, encephalitis, and reproductive disorders in various mammals. 2C protein is functionally indispensable and a promising target for drug development involving broad-spectrum picornaviral inhibitors. Here, an endogenous ATP molecule with a unique conformation was discovered by a combination of protein crystallography and high-performance liquid chromatography in the encephalomyocarditis virus (EMCV) 2C structure. Biochemical and structural characterization analysis of EMCV 2C revealed the critical role of conserved Arg311 in ATPase activity and self-oligomerization of EMCV 2C. The viral replication kinetics and infectivity study suggested that the residue negatively regulated the infectivity titer and virus encapsulation efficiency of EMCV and is, therefore, crucial for 2C protein to promote viral replication. Our systemic structure-function analysis provides unique insights into the function and regulation mechanism of cardioviral 2C protein., Competing Interests: The authors declare no conflict of interest.

The enzyme Asparaginyl Endopeptidase (AEP) is associated with proteinopathy-related pathologies such as Alzheimer's disease (AD) and Frontal Temporal Dementia (FTD). The onset of pathologies by AEP is due to cleaved fragments forming protein aggregates resulting in neurodegeneration. Unfortunately, there are no clinically approved small molecule inhibitors for AEP, and therefore, it serves as an unmet medical need for the design and development of potential novel small molecules. In developing potential inhibitors for proteolytic activity, a structured approach utilizing structure-based computer-aided drug design (SB-CADD) parameters was employed. This involved virtual high throughput screening (vHTS) across various CNS-focused databases enriched with diverse functionality. We identified the top sixty ligands based on the glide XP-docking score out of 10 million ligands. The free binding energy was then calculated using MM-GBSA for all top selected molecules which resulted in discovering that AEPI-1 to AEPI-6 (Asparaginyl Endopeptidase inhibitors) displayed high affinity towards the catalytic triad. Further investigation determined that all top six hits form stable complexes during 50 ns molecular dynamic simulations. We also observed that AEPI-2 demonstrated the highest stability within the binding pockets. Post-MD analyses such as DCCM, PCA, PDF, and ADMET properties were also evaluated. By bridging all the observations, we observed these six molecules occupy the active site of the β-helix (β1, β3, and β4) of the S1 pocket and additional binding sites in α1 and β5, suggesting its suitability as a potential candidate for drug discovery against Asparaginyl Endopeptidase.

Malaria is a disease caused mostly by Plasmodium falciparum, affects millions of people each year. The kinases are validated targets for malaria infection. In this study, we investigate for real and hypothetical compounds that can inhibit cyclic guanosine monophosphate (CGMP)-dependent protein kinase using molecular docking via combined similarity analysis, molecular dynamics simulations, quantitative structure activity relationship (QSAR). Using Tanimoto similarity scores, ∼8.4 million compounds were screened. Compounds that have at least 70% similarity are used in further analysis. These compounds are assessed by means of docking, MMBPSA, MMGBSA and ANI&#95;LIE. Based on consensus of different free energy methods and docking we revealed two potential inhibitors that can be useful for treatment of malaria. Apart from screening of real compounds, we have also selected the 10 most plausible hypothetical compounds by performing QSAR. By QSAR proposed pharmacophores, we generated over 247 hypothetical compounds and among them 19 molecules with lower QSAR predicted IC50 values and high docking scores were selected for further analysis. We selected the top 10 inhibitor candidates and performed MD simulations for free energy calculations like the protocol applied for real compounds. According to the free energy calculations, we suggest 2 real (C 34 H 29 F 5 N 8 O 4 S and C 30 H 27 F 2 N 7 O 2 S 2 , PubChem IDs: 140564801 and 89035196, respectively) and 2 hypothetical (C 23 H 27 FN 6 O 2 S, MOL3 and C 23 H 25 FN 6 O 2 S, MOL4) compounds that can be effective inhibitors against the protein kinase of Plasmodium falciparum.Communicated by Ramaswamy H. Sarma.

Global burden of breast cancer is expected to cross 26 million new cases by 2030. The term 'triple negative breast cancer' (TNBC) refers to lack of expression of hormone receptors (ER, PR and HER2). 5-Lipoxygenase (5-LOX) inhibition promotes breast cancer apoptosis, ferroptosis and inhibits metastases. Nuclear factor kappa B (NF-κB) activation induces cell survival in breast cancer through stimulation of angiogenesis. Therefore, inhibiting NF-B signalling can stop the growth of tumours. In light of these facts, an attempt is made to investigate binding characteristics of LOX inhibitors against 5-LOX (PDB-IDs 3V99 and 6N2W) and NF-κB (PDB-IDs 4KIK and 3DO7) through molecular docking, MM-GBSA calculation, molecular dynamic simulations (MDSs) and drug-likeness analysis. The eight lead molecules A169, A156, A162, A154, A102, A240, A86 and A58 were identified. The higher NF-B inhibiting potential of A169 was discovered through the sequential HTVS, SP docking and XP docking study. The hydrophobic interaction of Leu607, Phe610, Gln557 and Asn554 with 3V99 and Cys99, Glu97 and Arg20 of 4KIK is crucial for the inhibition. The LE, LLE and FQ values of A169 suggest their optimal binding with the target. This study strongly suggests the LOX and NF-κB inhibitory potential of A169, further lead optimisation and biological validation requires for the confirmations.Communicated by Ramaswamy H. Sarma.

Type II secretion System has been increasingly recognized as a key driver of virulence in many pathogenic bacteria including Achromobacter xylosoxidans. ATPase GspE is the powerhouse of the T2SS. It powers the entire secretion process by binding with ATP and hydrolyzing it. Therefore, targeting it was thought to have a profound effect on the normal functioning of the whole T2SS. A. xylosoxidans is a Gram-negative bacterium that poses a rising concern to immunocompromised people. It is responsible for many opportunistic infections mostly in people with cystic fibrosis. Due to its intrinsic and acquired resistance mechanisms, it is challenging to treat. In this current study, an extensive machine learning-enabled computational investigation was carried out. Drug libraries were screened using machine learning random forest algorithm trained on non-redundant dataset of 8722 antibacterial compounds with reported IC 50 values. Active compounds were then further subjected to molecular docking. To unravel the dynamics and better understand the stability of complexes, the top complexes were subjected to MD Simulations followed by various post-simulation analyses including Trajectory analysis, Atom Contacts, SASA, Hydrogen Bond, RDF, binding free energy calculations, PCA, and AFD analysis. Findings from the study unanimously unveiled Asinex-BAS00263070-28551 as the best inhibitor as it instigated the recursive dynamics of the target by making key hydrogen bond interactions with Walker A motif, suggesting it could serve as the promising drug candidate against GspE. Further experimental in-vivo and in-vitro validation is still required to authenticate the therapeutic effects of these drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

rAzoR2326, an azoreductase derived from Roseibium sp. H3510, functions as an FMN-dependent homodimer utilizing NADH as cofactor. It demonstrated maximum activity at 45 °C and retained moderate activity above 50 °C, exhibiting stability from pH 7-10. Evolution and structure guided rational design of wild-type rAzoR2326 (WT) efficiently yielded 6 single-point mutants with improved thermostability and activity from a 22-variant library. Further combinatorial mutation led to mutant M20 with substantially enhanced thermostability (15-fold longer half-life at 50 °C) and activity (3.24-fold higher k cat /K m ). M20 exhibited superior catalytic properties for decolorizing Allura Red compared to WT. Specifically, its decolorization capacity at pH 10.0 was 4.26-fold higher than WT. Additionally, M20 demonstrated remarkable thermostability, retaining 76.83 % decolorization activity for Allura Red after 120 min at 50 °C, whereas WT nearly lost all catalytic activity under the same conditions. Molecular dynamics simulations revealed the structural changes in M20, such as improved hydrogen bonding and a new C-H···π interaction, led to a more compact and rigid enzyme structure. This resulted in a more stable FMN-binding pocket and substrate tunnel, thereby improving the catalytic stability and activity of M20. Given its enhanced dye decolorization ability and alkaline tolerance, M20 shows promise as a biocatalyst for treating azo dye effluents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The human carbonic anhydrase (hCA) IX and XII isoforms are overexpressed in hypoxic conditions, contributing to cancer. Lack of isoform selectivity has been one of the main challenges associated with the existing drugs targeting hCAs. Hence, the development of alternative approaches, such as tail approach to develop more selective hCA IX and XII inhibitors is need of the hour. In the present work, we designed and synthesized 24 new 1,3.5-trisubstituted-pyrazoline derivatives with diverse substitutions. The synthesized analogs were evaluated for their hCA inhibitory activities against hCA I, II, IX, and XII isoforms. Among the tested compounds, derivative 8 displayed good inhibitory activity against hCA IX (K i  = 331 nM) and XII (K i = 96.7 nM). In addition, 9a-g also exhibited some inhibitory activities against hCA IX and XII, with K i s ranging from 574-799 nM and 137-369 nM, respectively. Molecular modelling studies of compound 8 displayed metal coordination with zinc ion and hydrophobic, hydrophilic interactions with adjacent amino acid residues, and maintained stable interactions throughout 100 ns. In addition, ADMET studies demonstrated that compound 8 obeyed the Lipinski's rule of five and was found to be druggable and non-toxic. Hence, compound 8 was identified as potential lead for further development., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

β-Glucuronidase, a crucial enzyme in drug metabolism and detoxification, represents a promising target for therapeutic intervention due to its potential to modulate drug pharmacokinetics and enhance therapeutic efficacy. Herein, we assessed the inhibitory potential of phytochemicals from Hibiscus trionum against β-glucuronidase. Grossamide and grossamide K emerged as the most potent β-glucuronidase inhibitors with IC 50 values of 0.73 ± 0.03 and 1.24 ± 0.03 μM, respectively. The investigated alkaloids effectively inhibited β-glucuronidase-catalyzed PNPG hydrolysis through a noncompetitive inhibition mode, whereas steppogenin displayed a mixed inhibition mechanism. Molecular docking analyses highlighted grossamide and grossamide K as inhibitors with the lowest binding free energy, all compounds successfully docked into the same main binding site occupied by the reference drug Epigallocatechin gallate (EGCG). We explored the interaction dynamics of isolated compounds with β-glucuronidase through a 200 ns molecular dynamics (MD) simulation. Analysis of various MD parameters revealed that grossamide and grossamide K maintained stable trajectories and demonstrated significant energy stabilization upon binding to β-glucuronidase. Additionally, these compounds exhibited the lowest average interaction energies with the target enzyme. The MM/PBSA calculations further supported these findings, showing the lowest binding free energies for grossamide and grossamide K. These computational results are consistent with experimental data, suggesting that grossamide and grossamide K could be potent inhibitors of β-glucuronidase., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Owing to its life cycle involving multiple hosts and species-specific biological complexities, a vaccine against Plasmodium , the causative agent of Malaria remains elusive. This makes chemotherapy the only viable means to address the clinical manifestations and spread of this deadly disease. However, rapid surge in antimalarial resistance poses significant challenges to our efforts to eliminate Malaria since the best drug available to-date; Artemisinin and its combinations are also rapidly losing efficacy. Sodium ATPase ( Pf ATP4) of Plasmodium has been recently explored as a suitable target for new antimalarials such as Cipargamin . Prior studies showed that multiple compounds from the Medicines for Malaria Venture (MMV) chemical libraries were efficient Pf ATP4 inhibitors. In this context, we undertook a structure- based virtual screening approach combined to Molecular Dynamic (MD) simulations to evaluate whether new molecules with binding affinity towards Pf ATP4 could be identified from the Pandemic Response Box (PRB), a 400-compound library of small molecules launched in 2019 by MMV. Our analysis identified new molecules from the PRB library that showed affinity for distinct binding sites including the previously known G358 site, several of which are clinically used anti-bacterial (MMV1634383, MMV1634402), antiviral (MMV010036, MMV394033) or antifungal (MMV1634494) agents. Therefore, this study highlights the possibility of exploiting PRB molecules against Malaria through abrogation of Pf ATP4 activity.Communicated by Ramaswamy H. Sarma.

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC 50 value of 0.40 ± 0.02 μM, ~2183-fold higher than acarbose having an IC 50 of 873.34 ± 1.67 μM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

The activation of caspases is central to apoptotic process in living systems. Defects in apoptosis have been implicated with carcinogenesis. Need to develop smart agents capable of inducing apoptosis in tumor cells is obvious. With this motive, diversity oriented synthesis of 1-benzylpyrrolidin-3-ol analogues was envisaged. The multi component Ugi reaction synthesized library of electronically diverse analogues was explored for cytotoxic propensity towards a panel of human cancer cell lines at 10 µM. The lead compounds exhibit a selective cytotoxicity towards HL-60 cells as compared to cell lines derived from solid tumors. Besides, their milder cytotoxic effect on non-cancerous cell lines reaffirm their selective action towards cancer cells only. The lead molecules were tested for their ability to target caspase-3, as a vital protease triggering apoptosis. The lead compounds were observed to induce apoptosis in HL-60 cells around 10 µM concentration. The lead compounds exhibited various non-covalent supra type interactions with caspase-3 key residues around the active site. The binding ability of lead compounds with caspase-3 was studied via molecular docking and molecular dynamic (MD) simulations. MD simulations indicated the stability of compound-caspase-3 complex throughout the 50 ns simulation run. The stability and bio-availability of the lead compounds under physiological conditions was assessed by their interaction with Bovine Serum Albumin (BSA) as model protein. BSA interactions of lead compounds were studied by various bio-physical methods and further substantiated with in silico MD simulations.

Abstract Background Canine circovirus is a deadly pathogen of dogs and causes vasculitis and hemorrhagic enteritis. It causes lethal gastroenteritis in pigs, fox, and dogs. Canine circovirus genome contains two main (and opposite) transcription units which encode two open reading frames (ORFs), a replicase-associated protein (Rep) and the capsid (Cap) protein. The replicase protein and capsid protein consist of 303 amino acids and 270 amino acids respectively. Several immuno-informatics methods such as epitope screening, molecular docking, and molecular-dynamics simulations were used to craft peptide-based vaccine construct against canine circovirus. Results The vaccine construct was designed by joining the selected epitopes with adjuvants by suitable linker. The cloning and expression of the vaccine construct was also performed using in silico methods. Screening of epitopes was conducted by NetMHC server that uses ANN (Artificial neural networking) algorithm. These methods are fast and cost-effective for screening epitopes that can interact with dog leukocyte antigens (DLA) and initiate an immune response. Overall, 5 epitopes, YQHLPPFRF, YIRAKWINW, ALYRRLTLI, HLQGFVNLK, and GTMNFVARR, were selected and used to design a vaccine construct. The molecular docking and molecular dynamics simulation studies show that these epitopes can bind with DLA molecules with stability. The codon adaptation and in silico cloning studies show that the vaccine can be expressed by Escherichia coli K12 strain. Conclusion The results suggest that the vaccine construct can be useful in preventing the dogs from canine circovirus infections. However, the results need further validation by performing other in vitro and in vivo experiments.

Coronavirus disease 2019 (COVID-19) is a pandemic whose adverse effects have been felt all over the world. As of August 2022, reports indicated that over 500 million people in the world had been infected and the number of rising deaths from the disease were slightly above 6.4 million. New variants of the causative agent, SARS-CoV-2 are emanating now and then and some are more efficacious and harder to manage. SARS-CoV-2 main protease (Mpro) has essential functions in viral gene expression and replication through proteolytic cleavage of polyproteins. Search for SARS-CoV-2 Mpro inhibitors is a vital step in the treatment and management of COVID-19. In this study, we investigated whether alkaloids with antiviral and myriad other bioactivities from the genus Lycoris can act as SARS-CoV-2 Mpro inhibitors. We conducted a computer-aided drug design study through screening optimal ligands for SARS-CoV-2 Mpro from a list of over 150 Lycoris alkaloids created from online databases such as ChEMBL, PubChem, ChemSpider, and published journal papers. The In silico study involved molecular docking of Lycoris alkaloids to SARS-CoV-2 Mpro active site, absorption, distribution, metabolism, elimination and toxicity (ADMET) screening and finally molecular dynamic (MD) simulations of the most promising ligand-SARS-CoV-2 Mpro complexes. The study identified 3,11-dimethoxy-lycoramine, narwedine, O-demethyllycoramine and epilycoramine as drug-like and lead-like Lycoris alkaloids with favorable ADMET properties and are very likely to have an inhibition activity on SARS-CoV-2 Mpro and may become potential drug candidates. DOI: http://dx.doi.org/10.5281/zenodo.7041808

Janus tyrosine kinase 3 (JAK3) is primarily expressed in immune cells and is needed for signaling by the common gamma chain (γc) family of cytokines. Abnormal JAK3 signal transduction can manifest as hematological disorders, e.g., leukemia, severe combined immunodeficiency (SCID) and autoimmune disease states. While regulatory JAK3 phosphosites have been well studied, here a functional proteomics approach coupling a JAK3 autokinase assay to mass spectrometry revealed ten previously unreported autophosphorylation sites (Y105, Y190, Y238, Y399, Y633, Y637, Y738, Y762, Y824, and Y841). Of interest, Y841 was determined to be evolutionarily conserved across multiple species and JAK family members, suggesting a broader role for this residue. Phospho-substitution mutants confirmed that Y841 is also required for STAT5 tyrosine phosphorylation. The homologous JAK1 residue Y894 elicited a similar response to mutagenesis, indicating the shared importance for this site in JAK family members. Phospho-specific Y841-JAK3 antibodies recognized activated kinase from various T-cell lines and transforming JAK3 mutants. Computational biophysics analysis linked Y841 phosphorylation to enhanced JAK3 JH1 domain stability across pH environments, as well as to facilitated complementary electrostatic JH1 dimer formation. Interestingly, Y841 is not limited to tyrosine kinases, suggesting it represents a conserved ubiquitous enzymatic function that may hold therapeutic potential across multiple kinase families.

The monkeypox virus (MPXV) is an enveloped, double-stranded DNA virus belonging to the genus Orthopox viruses. In recent years, the virus has spread to countries where it was previously unknown, turning it into a worldwide emergency for public health. This study employs a structural-based drug design approach to identify potential inhibitors for the core cysteine proteinase of MPXV. During the simulations, the study identified two potential inhibitors, compound CHEMBL32926 and compound CHEMBL4861364, demonstrating strong binding affinities and drug-like properties. Their docking scores with the target protein were −10.7 and −10.9 kcal/mol, respectively. This study used ensemble-based protein–ligand docking to account for the binding site conformation variability. By examining how the identified inhibitors interact with the protein, this research sheds light on the workings of the inhibitors’ mechanisms of action. Molecular dynamic simulations of protein–ligand complexes showed fluctuations from the initial docked pose, but they confirmed their binding throughout the simulation. The MMGBSA binding free energy calculations for CHEMBL32926 showed a binding free energy range of (−9.25 to −9.65) kcal/mol, while CHEMBL4861364 exhibited a range of (−41.66 to −31.47) kcal/mol. Later, analogues were searched for these compounds with 70% similarity criteria, and their IC50 was predicted using pre-trained machine learning models. This resulted in identifying two similar compounds for each hit with comparable binding affinity for cysteine proteinase. This study’s structure-based drug design approach provides a promising strategy for identifying new drugs for treating MPXV infections.

Amphiphilic peptides, such as Aß amyloids, can adsorb at an interface between two immiscible electrolyte solutions (ITIES). Based on previous work (vide infra), a hydrophilic/hydrophobic interface is used as a simple biomimetic system for studying drug interactions. The ITIES provides a 2D interface to study ion-transfer processes associated with aggregation, as a function of Galvani potential difference. Here, the aggregation/complexation behaviour of Aβ(1-42) is studied in the presence of Cu (II) ions, together with the effect of a multifunctional peptidomimetic inhibitor (P6). Cyclic and differential pulse voltammetry proved to be particularly sensitive to the detection of the complexation and aggregation of Aβ(1-42), enabling estimations of changes in lipophilicity upon binding to Cu (II) and P6. At a 1:1 ratio of Cu (II):Aβ(1-42), fresh samples showed a single DPV (Differential Pulse Voltammetry) peak half wave transfer potential (E1/2) at 0.40 V. Upon increasing the ratio of Cu (II) two-fold, fluctuations were observed in the DPVs, indicating aggregation. The approximate stoichiometry and binding properties of Aβ(1-42) during complexation with Cu (II) were determined by performing a differential pulse voltammetry (DPV) standard addition method, which showed two binding regimes. A pKa of 8.1 was estimated, with a Cu:Aβ1-42 ratio~1:1.7. Studies using molecular dynamics simulations of peptides at the ITIES show that Aβ(1-42) strands interact through the formation of β-sheet stabilised structures. In the absence of copper, binding/unbinding is dynamic, and interactions are relatively weak, leading to the observation of parallel and anti-parallel arrangements of β-sheet stabilised aggregates. In the presence of copper ions, strong binding occurs between a copper ion and histidine residues on two peptides. This provides a convenient geometry for inducing favourable interactions between folded β-sheet structures. Circular Dichroism spectroscopy (CD spectroscopy) was used to support the aggregation behaviour of the Aβ(1-42) peptides following the addition of Cu (II) and P6 to the aqueous phase.

The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib’s downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of −41.48 and −29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of −37.92 and −38.5 kJ/mol against ERBB and −41.2 and −46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies.

As deformation and defects are inevitable during the manufacture and service of graphene resonators, comprehensive molecular dynamic (MD) simulations are performed to investigate the vibrational properties of the defective single-layer graphene sheets (SLGSs) during tension. Perfect SLGSs, SLGSs with single vacancy, SLGSs with low-concentration vacancies, and SLGSs with high-concentration vacancies are considered, respectively. The frequencies of the perfect and defective SLGSs at different stretching stages are investigated in detail. The effects of different external forces are also taken into account to study the vibration properties of the defective SLGSs. Results show that the perfect and defective SLGSs both successively perform four stages, i.e., the elastic stage, the yield stage, the hardening stage, and the fracture stage during stretching, and the elastic properties of the SLGSs are insensitive to the vacancy defects, while the ultimate strain is noticeably reduced by the vacancies. The single vacancy has no effect on the vibration properties of SLGS, while the frequency decreases with the increasing vacancy concentration for SLGS at the elastic stage. The frequency of yielded SLGS with a certain vacancy concentration is almost constant even with a varying external force. [ABSTRACT FROM AUTHOR]

Herein, the curing kinetics and the glass transition temperature (Tg) of MXene/phenolic epoxy composites with two curing agents, i.e., 4,4-diaminodiphenyl sulfone (DDS) and dicyandiamine (DICY), are systematically investigated using experimental characterization, mathematical modeling and molecular dynamics simulations. The effect of MXene content on an epoxy resin/amine curing agent system is also studied. These results reveal that the MXene/epoxy composites with both curing agent systems conform to the SB(m,n) two-parameter autocatalytic model. The addition of MXene accelerated the curing of the epoxy composite and increased the Tg by about 20 K. In addition, molecular dynamics were used to simulate the Tg of the cross-linked MXene/epoxy composites and to analyze microstructural features such as the free volume fraction (FFV). The simulation results show that the introduction of MXene improves the Tg and FFV of the simulated system. This is because the introduction of MXene restricts the movement of the epoxy/curing agent system. The conclusions are in good agreement with the experimental results. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a pandemic whose adverse effects have been felt all over the world. As of August 2022, reports indicated that over 500 million people in the world had been infected and the number of rising deaths from the disease were slightly above 6.4 million. New variants of the causative agent, SARS-CoV-2 are emanating now and then and some are more efficacious and harder to manage. SARSCoV-2 main protease (Mpro) has essential functions in viral gene expression and replication through proteolytic cleavage of polyproteins. Search for SARS-CoV-2 Mpro inhibitors is a vital step in the treatment and management of COVID-19. In this study, we investigated whether alkaloids with antiviral and myriad other bioactivities from the genus Lycoris can act as SARS-CoV-2 Mpro inhibitors. We conducted a computer-aided drug design study through screening optimal ligands for SARS-CoV-2 Mpro from a list of over 150 Lycoris alkaloids created from online databases such as ChEMBL, PubChem, ChemSpider, and published journal papers. The In silico study involved molecular docking of Lycoris alkaloids to SARS-CoV-2 Mpro active site, absorption, distribution, metabolism, elimination and toxicity (ADMET) screening and finally molecular dynamic (MD) simulations of the most promising ligand-SARS-CoV-2 Mpro complexes. The study identified 3,11-dimethoxy-lycoramine, narwedine, O-demethyllycoramine and epilycoramine as drug-like and lead-like Lycoris alkaloids with favorable ADMET properties and are very likely to have an inhibition activity on SARSCoV-2 Mpro and may become potential drug candidates. [ABSTRACT FROM AUTHOR]

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MEL-type zeolite was selected as a typical porous material to theoretically capture the purification scenario of a model landfill leachate comprising PbCl2 and CuCl2 varying the pressure (2.4–48 MPa). Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) was applied to simulate the equilibrium state (0.5 ns) and dynamics of Pb2+, Cu2+ and Cl− and water molecules (4 ns). Overall, the flux through the MEL membrane was increased by the increase of pressure. Lennard-Jones potential was used to explain non-bonded interactions between the membrane and ions as well as water molecules, in terms of values of energy and snapshots were taken from the evolution of purification phenomenon. The molecular patterns of accumulation of ions in the vicinity of zeolitic membrane were also captured as functions of the energies of the interaction between the contaminants and porous membrane. Mean square displacement (MSD) variation was indicative of the effect of pressure on dynamics of heavy metal separation; higher energies obtained at higher pressures, as reflected in alteration of van der Waals (vdW) force between ions and water molecules. The membrane revealed rejection above 70% for Pb2+, and almost 100% against Cu2+ and Cl−, respectively. Density of water remained almost 1 g cm3, but depending on population of water molecules decreased after passage into the zeolite membrane. [ABSTRACT FROM AUTHOR]

A new set of interatomic potentials combining the Morse and Born–Mayer forms is developed via the empirical fitting and ab initio energy surface fitting for the wurtzite phase of ZnO. The fitting values are extracted from the lattice parameters, elastic constants, and energy difference for ZnO with rock-salt and wurtzite phases. The validity and reliability of the interatomic potentials are verified by means of the lattice dynamics, molecular dynamics, and first-principles methods, respectively. The lattice parameters, elastic properties, and structural stabilities of ZnO are accurately reproduced with the new potentials, and the volume ratio is evaluated at high temperature and pressure. The phase transition pressures of ZnO from wurtzite and zinc-blende phases to rock-salt phase are predicted successfully. In addition, the melting temperature is calculated by applying the single-phase and two-phase molecular dynamics simulations approaches for ZnO with wurtzite phase, where the crystallization temperature and coordination number are also investigated through the radial distribution function. Finally, the elastic properties, including bulk modulus, Young's modulus, shear modulus, sound velocity, and elastic anisotropy, of ZnO with wurtzite phase are also explored. [ABSTRACT FROM AUTHOR]

COVID-19 has recently grown to be pandemic all around the world. Therefore, efforts to find effective drugs for the treatment of COVID-19 are needed to improve humans' life quality and survival. Since the main protease (Mpro) of SARS-CoV-2 plays a crucial role in viral replication and transcription, the inhibition of this enzyme could be a promising and challenging therapeutic target to fight COVID-19. The present study aims to identify alkaloid compounds as new potential inhibitors for SARS-CoV-2 Mpro by the hybrid modeling analyses. The docking-based virtual screening method assessed a collection of alkaloids extracted from over 500 medicinal plants and sponges. In order to validate the docking process, classical molecular dynamic simulations were applied on selected ligands, and the calculation of binding free energy was performed. Based on the proper interactions with the active site of the SARS-CoV-2 Mpro, low binding energy, few side effects, and the availability in the medicinal market, two indole alkaloids were found to be potential lead compounds that may serve as therapeutic options to treat COVID-19. This study paves the way for developing natural alkaloids as stronger potent antiviral agents against the SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Enterobacter cloacae (EC) is a significant emerging pathogen that is occasionally associated with lung infection, surgical site infection, urinary infection, sepsis, and outbreaks in neonatal intensive care units. In light of the fact that there is currently no approved vaccine or therapeutic option for the treatment of EC, the current study was developed to concentrate on applications based on modern computational approaches to design a multi-epitope-based E. cloacae peptide vaccine (MEBEPV) expressing the antigenic determinants prioritized from the EC genome. Integrated computational analyses identified two potential protein targets (phosphoporin protein-PhoE and putative outer-membrane porin protein) for further exploration on the basis of pangenome subtractive proteomics and immunoinformatic in-depth examination of the core proteomes. Then, a multi-epitope peptide vaccine was designed, which comprised shortlisted epitopes that were capable of eliciting both innate and adaptive immunity, as well as the cholera toxin's B-subunit, which was used as an adjuvant in the vaccine formulation. To ensure maximum expression, the vaccine's 3D structure was developed and the loop was refined, improving the stability by disulfide engineering, and the physicochemical characteristics of the recombinant vaccine sequence were found to be ideal for both in vitro and in vivo experimentation. Blind docking was then used for the prediction of the MEBEPV predominant blinding mode with MHCI, MHCII, and TLR3 innate immune receptors, with lowest global energy of −18.64 kJ/mol, −48.25 kJ/mol, and −5.20 kJ/mol for MHC-I, MHC-II, and TLR-4, respectively, with docked complexes considered for simulation. In MD and MMGBSA investigations, the docked models of MEBEPV-TLR3, MEBEPV-MHCI, and MEBEPV-MHCII were found to be stable during the course of the simulation. MM-GBSA analysis calculated −122.17 total net binding free energies for the TLR3-vaccine complex, −125.4 for the MHC I-vaccine complex, and −187.94 for the MHC II-vaccine complex. Next, MM-PBSA analysis calculated −115.63 binding free energy for the TLR3-vaccine complex, −118.19 for the MHC I-vaccine complex, and −184.61 for the MHC II-vaccine complex. When the vaccine was tested in silico, researchers discovered that it was capable of inducing both types of immune responses (cell mediated and humoral) at the same time. Even though the suggested MEBEPV has the potential to be a powerful contender against E. cloacae-associated illnesses, further testing in the laboratory will be required before it can be declared safe and immunogenic. [ABSTRACT FROM AUTHOR]

A novel laccase gene isolated from Bacillus pumilus TCCC 11568 was expressed, and the recombinant laccase (rLAC) displayed maximal activity at 80 °C and at pH 6.0 against ABTS. rLAC maintained its structural integrity at a high temperature (355 K) compared to its tertiary structure at a low temperature (325 K), except for some minor adjustments of certain loops. However, those adjustments were presumed to be responsible for the formation of a more open access aisle that facilitated the binding of ABTS in the active site, resulting in a shorter distance between the catalytic residue and the elevated binding energy. Additionally, rLAC showed good thermostability (≤70 °C) and pH stability over a wide range (3.0–10.0), and displayed high efficiency in decolorizing azo dyes that are applicable to the food industry. This work will improve our knowledge on the relationship of structure–function for thermophilic laccase, and provide a candidate for dye effluent treatment in the food industry. [ABSTRACT FROM AUTHOR]

A quantitative structure-property relationship (QSPR) in-silico study was performed to develop a mathematical model that correlates 2D and 3D descriptors of 37 antioxidant lubricant additives (compounds) with their properties. A molecular dynamics simulation study was also carried out to access these additives' binding strength on diamond-like carbon (DLC) and steel crystal surfaces. Five novel antioxidant lubricant additives were designed from the information derived from the QSPR mathematical model’s high coefficient molecular descriptors. All the novel lubricant additive’s antioxidant properties were found to be better than our previous study, with the lubricant additive (Z)-3-(4-(5-amino-1-phenyl-1H-pyrazol-3-yl)-3,5-dimethylphenyl)-2-phenyl-5-(thiophen-2-ylmethylene)-3,5-dihydro-4H-imidazol-4-one found to possessed excellent antioxidant properties of 0.850281 total acid values (T.A.V 0.1g/L) than its co-additives. Moreover, all the designed additives dynamically bind to steel crystal surfaces excellently from our dynamic simulation study than the DLC crystal surface. The molecular dynamics simulation results were found to be better than the one reported by our previous study. This investigation will help synthesize novel and excellent antioxidant lubricant additives that will hinder the base oil from undergoing a complete oxidation cycle and meet environmental requirements as these novel additives do not contain Zinc and Phosphorus, which often rendered exhaust pipes catalytic converter inactive, thereby increasing environmental pollution.

Abstract Background Lipases (EC 3.1.1.3) catalyze the hydrolysis of oil into free fatty acids and glycerol forming the 3rd largest group of commercialized enzymes. Plant lipases grab attention recently because of their specificity, less production and purified cost, and easy availability. In silico approach is the first step to identify different genes coding for lipase in a most common indigenous plant, wheat, to explore the possibility of this plant as an alternative source for commercial lipase production. As the hierarchy organization of genes reflects an ancient process of gene duplication and divergence, many of the theoretical and analytical tools of the phylogenetic systematics can be utilized for comparative genomic studies. Also, in addition to experimental identification and characterization of genes, for computational genomic analysis, Arabidopsis has become a popular strategy to identify crop genes which are economically important, as Arabidopsis genes had been well identified and characterized for lipase. A number of articles had been reported in which genes of wheat have shown strong homology with Arabidopsis. The complete genome sequences of rice and Arabidopsis constitute a valuable resource for comparative genome analysis as they are representatives of the two major evolutionary lineages within the angiosperms. Here, in this in silico approach, Arabidopsis and Oryza sativa serve as models for dicotyledonous and monocotyledonous species, respectively, and the genomic sequence data available was used to identify the lipase genes in wheat. Results In this present study, Ensembl Plants database was explored for lipase producing gene present in wheat genome and 21 genes were screened down as they contain specific domain and motif for lipase (GXSXG). According to the evolutionary analysis, it was found that the gene TraesCS5B02G157100, located in 5B chromosome, has 58.35% sequence similarity with the reported lipase gene of Arabidopsis thaliana and gene TraesCS3A02G463500 located in the 3A chromosome has 51.74% sequence similarity with the reported lipase gene of Oryza sativa. Homology modeling was performed using protein sequences coded by aforementioned genes and optimized by molecular dynamic simulations. Further with the help of molecular docking of modeled structures with tributyrin, binding efficiency was checked, and the difference in energies (DE) was −9.83 kcal/mol and −6.67 kcal/mol, respectively. Conclusions The present work provides a basic understanding of the gene-encoding lipase in wheat, which could be easily accessible and used as a potent industrial enzyme. The study enlightens another direction which can be used further to explore plant lipases.

Despite the excellent separation performance of organic-inorganic hybrid membranes, such as mixed-matrix membranes, their commercial application remains challenging due to difficulties in uniformly dispersing inorganic fillers and achieving good interfacial contact over large areas. In this paper, we present high-performance, thin-film composite (TFC) membranes made from low-cost, all-organic materials using a commercially attractive and straightforward process for CO 2 capture. The TFC membranes were prepared on a porous polysulfone support using 2,4,6-triaminopyrimidine (TAP) dispersed in comb-shaped polymerized poly(oxyethylene methacrylate) (PPOEM), synthesized through a free radical polymerization process. The organic filler TAP functioned as a hydrogen bond inducer, controlling the free volume and reducing gas diffusivity, thereby enhancing CO 2 selectivity over larger gases such as N 2 and CH 4. Incorporating 2 wt% TAP significantly improved separation performance by primarily reducing N 2 and CH 4 permeances, achieving a CO 2 permeance of 1140 GPU, with CO 2 /N 2 and CO 2 /CH 4 selectivities of 43.3 and 15.0, respectively. The achieved performance significantly surpassed that of Pebax-based membranes and successfully met the target criteria for post-combustion CO 2 capture. Variations in free volume, molecule aggregation, hydrogen bonding, and interaction energies between gases and membranes were thoroughly investigated via molecular dynamic (MD) simulations. This high-performance TFC membrane, created through simple and facile methods using entirely organic materials, achieves commercial standards for post-combustion CO 2 capture. [Display omitted] • Low-cost, all-organic TFC membranes were developed utilizing hydrogen bonding. • TAP served as a hydrogen bond inducer, which reduced free volume and enhanced selectivity. • MD simulations confirmed changes in free volume, molecular aggregation, hydrogen bonding, and interaction energies. • PPOEM/TAP outperformed Pebax-based membranes and met the targets for post-combustion CO 2 capture. [ABSTRACT FROM AUTHOR]

[Display omitted] • Laccase and peroxidase from the L1 strain showed strong interaction with a few antibiotics. • Both the enzymes formed stable complexes with seven antibiotics out of 18 widely used. • The antibiotic degradation potential of L1 enzymes was higher than that of commercial enzymes. • The approach used here is helpful for exploring the bioremediation potential of enzymes. This study showcased the antibiotic degradation abilities of laccase and catalase-peroxidase from Bacillus ligniniphilus L1, an extremophile, against 18 common antibiotics using computationally guided approach. Molecular docking and simulation identified six enzyme-antibiotic complexes for laccase and four for catalase-peroxidase, demonstrating significant binding affinity and stability. Enzyme activity assays corroborated computational results, indicating both enzymes could degrade all tested antibiotics with varying efficiencies. L1 laccase outperformed commercial laccase against five antibiotics, notably vancomycin, levofloxacin, tobramycin, linezolid, and rifamycin, with enhanced degradation potential upon ABTS addition. Catalase-peroxidase from L1 exhibited superior degradation efficiency over commercial peroxidase against vancomycin, linezolid, tobramycin, and clindamycin. Overall, this study underscores the computational approach's utility in understanding enzyme-mediated antibiotic degradation, offering insights into environmental contaminant remediation. [ABSTRACT FROM AUTHOR]

[Display omitted] • PMA was used as an eco-friendly Pb-affinity depressant in copper-lead sulfide minerals flotation separation. • PMA selectively attenuated the floatability of galena in a weakly alkalized pulp. • Adsorption density of PMA on galena was greater than that on chalcopyrite. • PMA significantly weakened the adsorptive activity of SBX on galena. Utilization of novel and highly efficient organic depressants in separation of various minerals in flotation is always a research hotspot. Herein, polymaleic acid (PMA) was utilized as an eco-friendly depressant with high affinity for lead to effectively separate chalcopyrite from galena via the flotation method. Flotation trials showed that PMA, added at low dosages, could considerably depress galena, while chalcopyrite was minimally affected, thereby achieving the separation of both minerals. Adsorption tests indicated that PMA strongly and selectively adsorbed on galena than on chalcopyrite, which significantly reduced the reactive activity of xanthate on galena. These findings were supported by contact angle measurements. Surface properties investigations also corroborated the stronger adsorption of PMA observed on galena. Molecular dynamic simulations suggested that the introduction of PMA into an aqueous system resulted in the accumulation of water molecules on galena. Simultaneously, the adsorption strength of PMA on galena increased during the interaction process between PMA and galena. These effects altered the surface characteristics of galena and increased its surface hydrophilicity. The present work provides mechanistic insights into the separation of metallic sulfide minerals in the presence of organic acid via the flotation method. [ABSTRACT FROM AUTHOR]

• The sulfolane additive improves the oxidation stability of Li–S battery electrolyte. • The sulfolane molecule inhibits the shuttle effect of Li 2 S 4 , Li 2 S 6 and Li 2 S 8. • Design of electrolytes with improved performance at the microscopic level. Lithium–sulfur (Li–S) batteries, which have a high theoretical capacity and can be prepared using low-cost activation materials, are a promising alternative for realizing high-energy-density battery systems. However, the stability of the electrolyte and the shuttle effect caused by dissolved lithium polysulfides in the electrolyte prevent their practical application. Due to its non-flammability and high oxidation stability, sulfolane shows good promise for improving the oxidation stability and weakening the shuttle effect of Li–S electrolytes. In this work, the effects of a sulfolane additive on a Li–S battery electrolyte were revealed by density functional theory calculations and molecular dynamics simulations. The molecular orbitals, thermodynamics, and dynamics of the oxidation reaction were analyzed from the electron level. The addition of sulfolane lowers the HOMO energy level and the configuration energy difference, which leads to improved oxidation stability. Furthermore, sulfolane shows affinity to the S atoms close to Li, which correspond to low-order polysulfides. This affinity is confirmed by binding energy data and indicates that the addition of sulfolane inhibits the diffusion of Li 2 S 4 , Li 2 S 6 and Li 2 S 8. This work provides an analysis of the effects of sulfolane as an additive from the electron and molecular levels, which will promote a better understanding of Li–S battery systems and enable the design of improved electrolytes. [ABSTRACT FROM AUTHOR]