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We provide promising computational (in silico) data on phytochemicals (compounds 1–10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1–10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1–10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests. [ABSTRACT FROM AUTHOR]

We provide promising computational (in silico) data on phytochemicals (compounds 1–10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1–10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1–10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests.

Objective: To investigate the renoprotective effects of luteolin on diabetes in rats. Methods: One week after administration of streptozotocin 55 mg/kg intraperitoneally, rats were given 25, 50, and 75 mg/kg/day of luteolin orally for another eight weeks. At the end of the experiment, body weight, blood glucose level, biochemical parameters for renal function (serum creatinine, blood urea nitrogen, uric acid, serum albumin, and total protein), kidney histology, matrix metalloproteinase (MMP)-2, MMP-9, and histone deacetylase 2 (HDAC-2) expression, and malondialdehyde, myeloperoxidase, and hydroxyproline content in renal tissue were evaluated. High glucose-induced damage using NRK-52E cell line was studied to evaluate cell viability and metalloenzyme expression. Additionally, in silico studies including docking and molecular dynamics simulations were conducted. Results: MMP-2, MMP-9, and HDAC-2 expressions were significantly increased in high glucose-induced NRK-52E cells and the renal tissue of diabetic rats. However, these changes were reversed by luteolin at the administered doses. Additionally, luteolin significantly reduced oxidative stress, inflammation, and fibrosis, as well as improved biochemical parameters in diabetic rats. Furthermore, luteolin at the examined doses markedly alleviated diabetes-induced histopathological changes in renal tissues. Conclusions: Luteolin effectively attenuates streptozotocin-induced diabetic nephropathy in rats by inhibiting MMP-2, MMP-9, and HDAC-2 expression, and reducing oxidative stress and inflammation.

OBJECTIVE: The study aimed to evaluate the Withaferin-A against the drug target a-amylase, revealing its plausible mode of action and molecular-level interactions essential for this specific target inhibitory potential computational approach. MATERIALS AND METHODS: In this scenario, we used computational methods, including docking, molecular dynamics simulation, and model-building simulations, to elucidate the atomic-level details responsible for the inhibitory potential of Withaferin-A derived from W. somnifera. The studio visualizer software was used for the visualization of ligands, structures of the receptor, bond length, and rendering of the image. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics of phytochemicals were investigated. Crystal structure of protein receptors and ligands were generated. Semi-flexible docking was done using Autodock software. Docking was performed using the Lamarckian Genetic Algorithm (LGA). Molecular descriptors were evaluated, and the pharmacological properties of the phytochemicals were explored. Molecular dynamic simulations were analyzed at the atomic level. All the simulations were conducted under the same temperature, pressure, and volume circumstances over the simulated time scale. RESULTS: Withaferin-A has shown a strong binding affinity towards α-amylase as demonstrated with -9.79 Kcal/mol with 66.61 estimated nanomolecular IC50 value for plausible anti-obesity activity. Molecular-level relationships and knowledge obtained from this study indicate solid interactions with TYR59, ASP197, and HIS299 residues which are of high importance for future works related to computational screening of target-specific α-amylase inhibitors. The results from the analysis have revealed potential molecular-level interactions useful for further designing/discovering novel α-amylase inhibitors. CONCLUSIONS: The framework of the studied phytochemicals enables the rapid development of subsequent modifications that could result in more lead-like compounds with better inhibitory efficacy and selectivity for α-amylase. [ABSTRACT FROM AUTHOR]

The use of computer-aided drug design (CADD) for the identification of lead compounds in radiotracer development is steadily increasing. Traditional CADD methods, such as structure-based and ligand-based virtual screening and optimization, have been successfully utilized in many drug discovery programs and are highlighted throughout this review. First, we discuss the use of virtual screening for hit identification at the beginning of drug discovery programs. This is followed by an analysis of how the hits derived from virtual screening can be filtered and culled to highly probable candidates to test in in vitro assays. We then illustrate how CADD can be used to optimize the potency of experimentally validated hit compounds from virtual screening for use in positron emission tomography (PET). Finally, we conclude with a survey of the newest techniques in CADD employing machine learning (ML). [ABSTRACT FROM AUTHOR]

Background: Nicastrin is a confirmed breast cancer target, but the lack of knowledge about its binding sites and the structural basis of interactions with known small molecules makes the development of small molecules against it challenging. Methods: Molecular docking and molecular dynamics simulations were used in this work to identify binding sites in nicastrin, a gamma-secretase component that has been implicated in breast cancer and a potential drug target in cancer chemotherapy. Results: Docking calculations identified three binding sites, however binding site analysis using druggability assessment identified a region that encompasses the DYIGS motif, the DYIGS site as the most favorable binding site. This site was validated by a 50 ns molecular dynamics simulation with a known inhibitor CID44433923 and free energy of binding was found to be -11.4 kcal/mol and mainly driven by hydrophobic interactions. Per residue decomposition analysis showed that Gln139, Val138 and Arg105 had a relatively high contribution towards the free energy of binding. These results suggest that these residues might be critical in nicastrin inhibition. Binding mode analysis by docking previously reported nicastrin inhibitors identified residues Gln139, Val138 and Asp143 as key in the interactions. Conclusions: This work affords an insight into the binding mechanism of small molecules and might direct drug design efforts towards nicastrin.

Chronic Myeloid Leukemia (CML) is known as clonal myeloproliferative disorder resulted by the proliferative and deregulated expression of the BCR-ABL gene. Although targeting the BCR-ABL gene is an effective treatment for CML, the development of drug intolerance and drug resistance is still an issue for BCR-ABL targeted therapy. With an aim to develop novel BCR-ABL inhibitors with fewer side effects, we started with the anti-cancerous natural compound coumestrol as the lead. Chalcone and pyrazole are the well-exploited scaffolds in the anticancer domain; hence, in this work, we designed novel coumestrol derivatives with these structures. In order to quantify the structural changes, we employed in silico methods. The new drug leads were compared with the FDA-approved CML drug bosutinib. The molecular orbital analysis of the selected lead compounds was assessed by Density Functional Theory (DFT) approach. Molecular Dynamic (MD) computations were performed on the most promising leads to find the stability. Following which, the pharmacokinetics parameters of the screened compounds were also analyzed to check the drug-like property. Although targeting the BCR-ABL gene is an effective treatment for Chronic myeloid leukaemia (CML), the development of drug intolerance and drug resistance are still an issue for BCR-ABL targeted therapy. With an aim to develop novel BCR-ABL inhibitors with fewer side effects, we designed some molecules by incorporating chalcone and pyrazole moieties into the anti-cancerous natural compound coumestrol. In-silico simulations were used to predict their activities and compared these results with the activities predicted for the FDA-approved CML drug bosutinib. [ABSTRACT FROM AUTHOR]

In response to the COVID-19 pandemic, and the lack of effective and safe antivirals against it, we adopted a new approach in which food supplements with vital antiviral characteristics, low toxicity, and fast excretion have been targeted. The structures and chemical properties of the food supplements were compared to the promising antivirals against SARS-COV-2. Our goal was to exploit the food supplements to mimic the topical antivirals' functions but circumventing their severe side effects, which has limited the necessary dosage needed to exhibit the desired antiviral activity. On this line, after a comparative structural analysis of the chemicals mentioned above, and investigation of their potential mechanisms of action, we selected caffeine and some compounds of the vitamin B family and further applied molecular modeling techniques to evaluate their interactions with the RDB domain of the Spike protein of SARS-CoV-2 (SC2Spike) and its corresponding binding site on human ACE-2 (HssACE2). Our results pointed to vitamins B1 and B6 in the neutral form as potential binders to the HssACE2 RDB binding pocket that might be able to impair the SARS-CoV-2 mechanism of cell invasion, qualifying as potential leads for experimental investigation against COVID-19. [ABSTRACT FROM AUTHOR]

Sclerostin (SOST), a Wnt signaling pathway inhibitor, is involved in the pathogenesis of skeletal disorders. This study investigated the impact of the GKWWRPS motif on the PNAIG motif in Loop 2 of SOST, which is accountable for the interactions with the LRP6 protein that triggers the down-regulation of the Wnt signaling pathway. Single amino acid mutations on the GKWWRPS motif, hypothesized to have a probable stabilization effect towards the PNAIG motif, led to a significant reduction in the primary interactions between the SOST and LRP6 proteins. Protein-protein docking and molecular dynamic studies were conducted to investigate the role of the motif. The study found that a solitary mutation in the GKWWRPS motif significantly reduced the primary interactions between SOST and LRP6 proteins, except for probable cold-spot residues. The study's findings establish the GKWWRPS motif as a promising target for therapeutic interventions. Based on the obtained results, it can be inferred that alterations implemented within the GKWWRPS motif could lead to the destabilization of the PNAIG motif, which would directly modulate the interactions between the SOST and LRP6 proteins. The present investigation thus presents novel opportunities in the field of anti-sclerostin interventions. [Display omitted] [ABSTRACT FROM AUTHOR]

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

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]

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.

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. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease Mpro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential Mpro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 Mpro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards Mpro, with an IC50 values range of 0.36–0.89 µM comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent Mpro inhibitors.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is a novel coronavirus strain that emerged at the end of 2019, causing millions of deaths so far. Despite enormous efforts being made through various drug discovery campaigns, there is still a desperate need for treatments with high efficacy and selectivity. Recently, marine sulfated polysaccharides (MSPs) have earned significant attention and are widely examined against many viral infections. This article attempted to produce a comprehensive report about MSPs from different marine sources alongside their antiviral effects against various viral species covering the last 25 years of research articles. Additionally, these reported MSPs were subjected to molecular docking and dynamic simulation experiments to ascertain potential interactions with both the receptor-binding domain (RBD) of SARS CoV-2’s spike protein (S-protein) and human angiotensin-converting enzyme-2 (ACE2). The possible binding sites on both S-protein’s RBD and ACE2 were determined based on how they bind to heparin, which has been reported to exhibit significant antiviral activity against SARS CoV-2 through binding to RBD, preventing the virus from affecting ACE2. Moreover, our modeling results illustrate that heparin can also bind to and block ACE2, acting as a competitor and protective agent against SARS CoV-2 infection. Nine of the investigated MSPs candidates exhibited promising results, taking into consideration the newly emerged SARS CoV-2 variants, of which five were not previously reported to exert antiviral activity against SARS CoV-2, including sulfated galactofucan (1), sulfated polymannuroguluronate (SPMG) (2), sulfated mannan (3), sulfated heterorhamnan (8), and chondroitin sulfate E (CS-E) (9). These results shed light on the importance of sulfated polysaccharides as potential SARS-CoV-2 inhibitors.

Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound 20b showed to be a potent MAGL reversible inhibitor (IC50 = 348 nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL.

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

Protein kinase D 1 (PKD1) overexpression has a well-validated role in cancer progression and its inhibitors have defined a protective role-play of PKD1 for various cancers such as prostate, pancreatic and noninvasive breast cancers, and more. Therefore, the current research was aimed at designing new PKD1 inhibitors combining different ligand- and structure-based computational drug designing methodologies. Initially, the three-dimensional structure of PKD1's active site was computationally modeled, corrected using molecular dynamic simulations and validated for docking experiments. The highest active PKD1 inhibitor was used to develop a structure-based energetic pharmacophore (e-pharmacophore) model, and a final model was selected with five structural features (Pmodel_AADHR). Pmodel_AADHR was validated and used for database screening to obtain new hits against PKD1. These newly retrieved hits were docked against our PKD1 protein model, and those displaying essential interactions are reported herein as new hits, which could serve as new leads for cancer research, especially pancreatic cancer. [ABSTRACT FROM AUTHOR]

Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are important drug targets for the treatment of neurological diseases. However, the precise determinants of the binding efficacies of ligands for these receptors are unclear. Therefore, in this study, the binding energy profiles of various ligands (full agonists, partial agonists, and antagonists) were quantified by docking those ligands with structural ensembles of the α7 nAChR exhibiting different degrees of C-loop closure. This approximate treatment of interactions suggested that full agonists, partial agonists, and antagonists of the α7 nAChR possess distinctive binding energy profiles. Results from docking revealed that ligand binding efficacy may be related to the capacity of the ligand to stabilize conformational states with a closed C loop. [ABSTRACT FROM AUTHOR]

The BCR-ABL fusion gene is one of the major causes of 95% of Chronic Myeloid Leukemia (CML). While, BCR-ABL protein is currently being used as a major target to treat CML. Although, current FDA-approved drugs such as; Imatinib and Nilotinib have stupendously improved the patients 5-year’s survival rates, the drug resistance has dramatically reduced their effects. So, more accurate and effective alternative treatments are crucially needed. To address this issue, we screened the FDA-approved drugs by virtual screening and binding free energy calculations to identify new inhibitors for the wild-type and T315I gatekeeper mutant ABL1. It was invigorating to identify that chlorohexidine, paromomycin and deferoxamine could inhibit the wild-type ABL1, while chlorohexidine and ritonavir could inhibit the T315I mutant ABL1. The applications of these newly identified drugs are not just an effortless hypothesis in drug discovery. These drugs can be evaluated in phase 2 clinical trials after a simple kinase selectivity assay. [ABSTRACT FROM AUTHOR]

Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound20bshowed to be a potent MAGL reversible inhibitor (IC50 = 348 nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL. [ABSTRACT FROM PUBLISHER]

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of benzothiazole-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I and hCA II and the transmembrane hCA IX and hCA XII. Several of the investigated derivatives showed interesting inhibition activity and selectivities for inhibiting hCA IX and hCA XII over the off-target ones hCA I and hCA II. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX. [ABSTRACT FROM PUBLISHER]

[Display omitted] • Indole-carbohydrazide moieties with different aryl substitutions were designed, synthesized, and screened as tyrosinase inhibitors. • Compounds bearing para -hydroxybenzyl moiety exhibited superior tyrosinase inhibitory activities with IC 50 values of 0.007, 0.072, and 0.19 µM. • Molecular docking analyses and molecular dynamic simulations were also performed to anticipate critical interaction between potent derivatives and the binding site of tyrosinase. In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC 50 values in the range of 0.070 to > 100 μM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC 50 = 0.070 μM), 8f (R = 4-OH, IC 50 = 0.072 μM), and 19e (IC 50 = 0.19 μM) with para -OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 μM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281. [ABSTRACT FROM AUTHOR]

Heat shock protein90s (Hsp90s) play a crucial role in the development of cancer, and their inhibitors are a main target for tumor suppression. P53 also is a tumor suppressor, but in cancer cells, mutations in the p53 gene lead to the inactivation and accumulation of protein. For instance, the ninth p53 cancer mutation, Y220C, destabilizes the p53 core domain. Small molecules have been assumed to bind to Y220C DNA-binding domain and reactivate cellular mutant p53 functions. In this study, one of the mutant p53 activators is suggested as an Hsp90 inhibitor according to a pyrazole scaffold. To confirm a new ligand as a dual agent, molecular docking and molecular dynamic simulations were performed on both proteins (p53 and Hsp90). Molecular dynamic simulations were also conducted to evaluate the obtained results on the other two pyrazole structures, one known as Hsp90 inhibitor and the other as the reported mutant p53 activator. The findings indicate that the new ligand was stable in the active site of both proteins. Finally, a virtual screening was performed on ZINC database, and a set of new dual agents was proposed according to the new ligand scaffold. [ABSTRACT FROM AUTHOR]

Neuraminidase (NA) is a membrane surface antigen which helps in the release of influenza viruses from the host cells after replication. Anti-influenza drugs such as zanamivir bind with eight highly conserved functional residues (R118, D151, R152, R224, E276, R292, R371, and Y406) in the active site of NA, thus restricting the viral release the from host cells. Binding of the drug in active site inhibits the ability of enzyme to cleave sialic acid residues on the cell membrane. Reports on the emergence of zanamivir-resistant strains of H1N1 Influenza virus necessitated a search for alternative drug candidates, preferably from plant source due to their known benefits such as less or no side effects, availability, and low cost. Withaferin A (WA), an active constituent of Withania somnifera ayurvedic herb, has been shown to have a broad range of medicinal properties including its anti-viral activity. The present study demonstrated that WA has the potential to attenuate the neuraminidase of H1N1 influenza. Our docking and simulation results predicted high binding affinity of the WA toward NA and revealed several interesting molecular interactions with the residues which are catalytically important during molecular dynamic simulations. The results presented in the article could be of high importance for further designing of target-specific anti-influenza drug candidates. [ABSTRACT FROM AUTHOR]

We describe the conformational behavior of histone deacetylase 8 (HDAC8) using molecular dynamics (MD) simulations. HDAC8 conformers were used for the docking studies using some known HDAC inhibitors (HDACi) suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA), aroyl-pyrrole-hydroxy-amide (APHA-8) and tubacin to explore their interactions, binding modes, free energy values. The MD simulation show that HDAC8 make important surface changes at the catalytic site (CS) entrance as well as at two entrances locations in the 14-Å tunnel. In addition, we identify an alternate entrance to the 14-Å tunnel named adjacent to the catalytic site pocket (ACSP). By using docking studies, it was possible to elucidate the importance of hydrophobic and π-π interactions that are the most important for the ligand-HDAC8 complex structural stabilization. In conclusion, the ligand flexibility, molecular weight and chemical moieties (hydroxamic acid, aryl and aliphatic moieties) are the principal properties required to increase the binding affinity on HDAC8. [ABSTRACT FROM AUTHOR]

Acetyl-CoA carboxylase (ACCase), a biotin-dependent enzyme that catalyses the first committed step of fatty acid biosynthesis, is considered as a potential target for improving lipid accumulation in oleaginous feedstocks, including microalgae. ACCase is composed of three distinct conserved domains, and understanding the structural details of each catalytic domain assumes great significance to gain insights into the molecular basis of the complex formation and mechanism of biotin transport. In the absence of a crystal structure for any single heteromeric ACCase till date, here we report the first heteromeric association model of ACCase from an oleaginous green microalga, Chlorella variabilis, using a combination of homology modelling, docking and molecular dynamic simulations. The binding site of the docked biotin carboxylase (BC) and carboxyltransferase (CT) were predicted to be contiguous but distinct in biotin carboxyl carrier protein (BCCP) molecule. Simulation studies revealed considerable flexibility for the BC and CT domains in the BCCP-bound forms, thus indicating the adaptive behaviour of BCCP. Further, principal component analysis revealed that in the presence of BCCP, the BC and CT domains exhibited an open-state conformation via the outward clockwise rotation of the binding helices. These conformational changes might be responsible for binding of BCCP domain and its translocation to the respective active sites. Various rearrangements of inter-domain hydrogen bonds (H-bonds) contributed to conformational changes in the structures. H-bond interactions between the interacting residue pairs involving Glu201BCCP/Arg255BC and Asp224BCCP/Gln228CT were found to be essential for the intermolecular assembly. The present findings are consistent with previous biochemical studies. [ABSTRACT FROM AUTHOR]

Abstract: A set of sulfamides and sulfamates were synthesized and tested against several isoforms of carbonic anhydrase: CA I, CA II, CA VII, CA XII and CA XIV. The biological assays showed a broad range of inhibitory activity, and interesting results were found for several compounds in terms of activity (K i <1μm) and selectivity: some aromatic sulfamides are active against CA I, CA II and/or CA VII; while they are less active in CA XII and CA XIV. On the other hand, bulky sulfamides are selective to CA VII. To understand the origin of the different inhibitory activity against each isozyme we used molecular modeling techniques such as docking and molecular dynamic simulations. [Copyright &y& Elsevier]

SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease Mpro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential Mpro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 Mpro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards Mpro, with an IC50 values range of 0.36–0.89 µM comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent Mpro inhibitors. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is a novel coronavirus strain that emerged at the end of 2019, causing millions of deaths so far. Despite enormous efforts being made through various drug discovery campaigns, there is still a desperate need for treatments with high efficacy and selectivity. Recently, marine sulfated polysaccharides (MSPs) have earned significant attention and are widely examined against many viral infections. This article attempted to produce a comprehensive report about MSPs from different marine sources alongside their antiviral effects against various viral species covering the last 25 years of research articles. Additionally, these reported MSPs were subjected to molecular docking and dynamic simulation experiments to ascertain potential interactions with both the receptor-binding domain (RBD) of SARS CoV-2's spike protein (S-protein) and human angiotensin-converting enzyme-2 (ACE2). The possible binding sites on both S-protein's RBD and ACE2 were determined based on how they bind to heparin, which has been reported to exhibit significant antiviral activity against SARS CoV-2 through binding to RBD, preventing the virus from affecting ACE2. Moreover, our modeling results illustrate that heparin can also bind to and block ACE2, acting as a competitor and protective agent against SARS CoV-2 infection. Nine of the investigated MSPs candidates exhibited promising results, taking into consideration the newly emerged SARS CoV-2 variants, of which five were not previously reported to exert antiviral activity against SARS CoV-2, including sulfated galactofucan (1), sulfated polymannuroguluronate (SPMG) (2), sulfated mannan (3), sulfated heterorhamnan (8), and chondroitin sulfate E (CS-E) (9). These results shed light on the importance of sulfated polysaccharides as potential SARS-CoV-2 inhibitors. [ABSTRACT FROM AUTHOR]

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment. [ABSTRACT FROM AUTHOR]

Infections due to resistant bacteria are the life-threatening and leading cause of mortality worldwide. The current therapy for bacterial infections includes treatment with various drugs and antibiotics. The misuse and over usage of these antibiotics leads to bacterial resistance. There are several mechanisms by which bacteria exhibit resistance to some antibiotics. These include drug inactivation or modification, elimination of antibiotics through efflux pumps, drug target alteration, and modification of metabolic pathway. However, it is difficult to treat infections caused by resistant bacteria by conventional existing therapy. In the present study binding affinities of some glitazones against ParE and MurE bacterial enzymes are investigated by in silico methods. As evident by extra-precision docking and binding free energy calculation (MM-GBSA) results, rivoglitazone exhibited higher binding affinity against both ParE and MurE enzymes compared to all other selected compounds. Further molecular dynamic (MD) simulations were performed to validate the stability of rivoglitazone/4MOT and rivoglitazone/4C13 complexes and to get insight into the binding mode of inhibitor. Thus, we hypothesize that structural modifications of the rivoglitazone scaffold can be useful for the development of an effective antibacterial agent. [ABSTRACT FROM AUTHOR]