Repurposing of anti-lung cancer drugs as multi-target inhibitors of SARS-CoV-2 proteins: An insight from molecular docking and MD-simulation study

The main objective of this research is to identify potential leads for developing potent Keap1 inhibitors. In the current research article, in-silico methods have been employed to discover potential Keap1 inhibitors. 3D-QSAR was generated using the ChemBL database of Keap1 inhibitors with IC50. The best pharmacophore was selected for the screening of three different libraries namely Asinex, MiniMaybridge, and Zinc. The molecules screened from the databases were filtered through druggability rules and molecular docking studies. The best binding molecules obtained after docking studies were subjected to physicochemical properties toxicity determination by in-silico methods. The best hits were studied for stability in the cavity of Keap1 by molecular dynamic simulations. The virtual screening of different databases was carried out separately and three leads, were obtained. These lead molecules ASINEX 508, MiniMaybridgeHTS_01719, and ZINC 0000952883 showed the best binding in the Keap1 cavity. The molecular dynamic simulations of the binding complexes of the leads support the docking analysis. The leads (ASINEX 508, MiniMaybridgeHTS_01719, and ZINC 0000952883) were stabilized in the Keap1 binding cavity throughout 100 ns simulation, with average RMSD values of 0.100, 0.114, and 0.106 nm, respectively. This research proposes three lead molecules as potential Keap1 inhibitors based on high throughput screening, docking, and MD simulation studies. These hit molecules can be used for further design and development of Keap1 inhibitors. This research provides the preliminary data for discovering novel Keap1 inhibitors. It opens new avenues for medicinal chemists to explore antioxidant-stimulating molecules targeting the Keap1-Nrf2 pathway.

A series of novel 24 phenylhydrazono phenoxyquinoline derivatives were synthesized with moderate to excellent yield and screened for their efficacy against the α-amylase enzyme through in silico studies. The structures were characterized using spectroscopic techniques such as 1HNMR, 13CNMR, and HREI-MS. Comprehensive computational studies including, drug-likeness and ADMET profiling, quantum chemical calculations, molecular docking, and molecular dynamics (MD) simulation studies, were performed. A density functional theory study of the synthesized compounds indicated a favorable reactivity profile. The synthesized novel analogues were docked against α-amylase (PDB 6OCN) enzymes to investigate the binding interactions. Based on the docking studies, one of the compounds was found to be the hit with the highest negative binding affinity for α-amylase. A MD simulation study indicated stable binding throughout the simulation.

Outbreak of Coronavirus (SARS-CoV-2) has thrown a big challenge to the globe by snatching millions of human lives from the world. In this study, inhibitory efficiency of ten anti-HIV compounds from different Indian medicinal plant parts have been virtually screened against Mpro, PLpro and RdRp proteins of SARS-CoV-2. The molecular docking study reflected that among these compounds, Proptine (PTP) has the highest binding affinity for the three cases. Introduction of PTP molecules within the binding pocket of these proteins showed a large structural and conformational changes on the structure of proteins which is revealed from molecular dynamics (MD) simulation studies. RMSD, RMSF and analysis of thermodynamic parameters also revealed that PTP makes a huge impact on the structures of the respective proteins which will pave an opportunity for doing advanced experimental research to evaluate the potential drug to combat COVID-19.Graphic abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s13721-021-00309-3.

Ulcers due to infections with Mycobacterium ulcerans are characterized by complete lack of wound healing processes, painless, an underlying bed of host dead cells and undermined edges due to necrosis. Mycolactone, a macrolide produced by the mycobacterium, is believed to be the toxin responsible. Of interest and relevance is the knowledge that Buruli ulcer (BU) patients remember experiencing trauma previously at the site of the ulcers, suggesting an impairment of wound healing processes, the plausible effect due to the toxin. Wound healing processes involve activation of the blood platelets to release the contents of the dense granules mainly serotonin, calcium ions, and ADP/ATP by exocytosis into the bloodstream. The serotonin release results in attracting more platelets and mast cells to the wound site, with the mast cells also undergoing degranulation, releasing compounds into the bloodstream by exocytosis. Recent work has identified interference in the co-translational translocation of many secreted proteins via the endoplasmic reticulum and cell death involving Wiskott-Aldrich syndrome protein (WASP), Sec61, and angiotensin II receptors (AT2R). We hypothesized that mycolactone by being lipophilic, passively crosses cell membranes and binds to key proteins that are involved in exocytosis by platelets and mast cells, thus inhibiting the initiation of wound healing processes. Based on this, molecular docking studies were performed with mycolactone against key soluble n-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and regulators, namely Vesicle-associated membrane protein (VAMP8), Synaptosomal-associated protein (SNAP23, syntaxin 11, Munc13-4 (its isoform Munc13-1 was used), and Munc18b; and also against known mycolactone targets (Sec61, AT2R, and WASP). Munc18b was shown to be a plausible mycolactone target after the molecular docking studies with binding affinity of −8.5 kcal/mol. Structural studies and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding energy calculations of the mycolactone and Munc18b complex was done with 100 ns molecular dynamics simulations using GROMACS. Mycolactone binds strongly to Munc18b with an average binding energy of −247.571 ± 37.471 kJ/mol, and its presence elicits changes in the structural conformation of the protein. Analysis of the binding interactions also shows that mycolactone interacts with Arg405, which is an important residue of Munc18b, whose mutation could result in impaired granule exocytosis. These findings consolidate the possibility that Munc18b could be a target of mycolactone. The implication of the interaction can be experimentally evaluated to further understand its role in granule exocytosis impairment in Buruli ulcer.

Kinesin Eg5 plays an essential role in the early stages of mitosis, and it is an interesting drug target for the design of potent inhibitors. In this work, combined molecular modeling studies of molecular docking, receptor-guided QSAR methodology, and molecular dynamics (MD) simulation were performed on a series of novel S-trityl-l-cysteine (STLC) analogues as Eg5 inhibitors to understand the structural features and key residues which are involved in the inhibition. Molecular docking study was used to find the actual conformations of STLC analogues in the binding site of Eg5. Multiple linear regression (MLR), artificial neural network (ANN), and support vector machine (SVM) models were developed by the conformation which was obtained by performing docking studies. The satisfactory result of the SVM model (R2 = 0.962, SE = 0.210, RMSE = 0.190, and Q2LOO = 0.930) demonstrated the superiority of this model over other models. Also, the satisfactory agreement between experiment and predicted inhibitory values suggested that the SVM model represents good correlation and predictive power. Molecular docking was used to study the functionalities of active molecular interaction between inhibitors and Eg5. Moreover, molecular dynamics (MD) simulation was performed on the best inhibitor-Eg5 complex to investigate the stability of docked conformation and to study the binding interactions in detail. The MD simulation result showed four hydrogen bond interactions with Eg5 residues including Gly117, Glu116, Gly117, and Glu118. The outcome of this study can be used as a guideline to better interpret the protein-ligand interaction and also can assist in the designing and development of more potent Eg5 inhibitors.

Diabetic Kidney Disease (DKD), a frequent consequence of diabetes, has substantial implications for both morbidity and mortality rates, prompting the exploration of new metabolic biomarkers due to limitations in current methods like creatinine and albumin measurements. Pentraxin 3 (PTX3) shows promise for assessing renal inflammation in DKD. This study investigates how DKD metabolites could influence PTX3 expression through molecular docking, ADMET profiling, and dynamic simulation. Network and pathway analyses were conducted to explore metabolite interactions with DKD genes and their contributions to DKD pathogenesis. Thirty-three DKD-associated metabolites were screened, using pentoxifylline (PEN) as a reference. The pharmacokinetic properties of these compounds were evaluated through molecular docking and ADMET profiling. Molecular dynamics simulations over 200 ns assessed the stability of PTX3 (apo), the PRE-PTX3 complex, and PEN-PTX3 across multiple parameters. Cytoscape identified 1082 nodes and 1381 edges linking metabolites with DKD genes. KEGG pathway analysis underscored PTX3's role in inflammation. Molecular docking revealed pregnenolone sulfate (PRE) with the highest binding affinity (-6.25 kcal/mol), followed by hydrocortisone (-6.03 kcal/mol) and 2-arachidonoylglycerol (-5.92 kcal/mol), compared to PEN (-5.35 kcal/mol). ADMET profiling selected PRE for dynamic simulation alongside PEN. Analysis of RMSD, RMSF, RG, SASA, H-bond, PCA, FEL, and MM-PBSA indicated stable complex behavior over time. Our findings suggest that increasing PRE levels could be beneficial in managing DKD, potentially through isolating PRE from fungal sources, synthesizing it as dietary supplements, or enhancing endogenous PRE synthesis within the body.

COVID-19 (Coronavirus disease 2019) is a transmissible disease initiated and propagated through a new virus strain SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) since 31st December 2019 in Wuhan city of China and the infection has outspread globally influencing millions of people. Here, an attempt was made to recognize natural phytochemicals from medicinal plants, in order to reutilize them against COVID-19 by the virtue of molecular docking and molecular dynamics (MD) simulation study. Molecular docking study showed six probable inhibitors against SARS-CoV-2 Mpro (Main protease), two from Withania somnifera (Ashwagandha) (Withanoside V [10.32 kcal/mol] and Somniferine [9.62 kcal/mol]), one from Tinospora cordifolia (Giloy) (Tinocordiside [8.10 kcal/mol]) and three from Ocimum sanctum (Tulsi) (Vicenin [8.97 kcal/mol], Isorientin 4′-O-glucoside 2″-O-p-hydroxybenzoagte [8.55 kcal/mol] and Ursolic acid [8.52 kcal/mol]). ADMET profile prediction showed that the best docked phytochemicals from present work were safe and possesses drug-like properties. Further MD simulation study was performed to assess the constancy of docked complexes and found stable. Hence from present study it could be suggested that active phytochemicals from medicinal plants could potentially inhibit Mpro of SARS-CoV-2 and further equip the management strategy against COVID-19-a global contagion. Highlights Holistic approach of Ayurvedic medicinal plants to avenge against COVID-19 pandemic. Active phytoconstituents of Ayurvedic medicinal plants Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi) predicted to significantly hinder main protease (Mpro or 3Clpro) of SARS-CoV-2. Through molecular docking and molecular dynamic simulation study, Withanoside V, Somniferine, Tinocordiside, Vicenin, Ursolic acid and Isorientin 4′-O-glucoside 2″-O-p-hydroxybenzoagte were anticipated to impede the activity of SARS-CoV-2 Mpro. Drug-likeness and ADMET profile prediction of best docked compounds from present study were predicted to be safe, drug-like compounds with no toxicity. Communicated by Ramaswamy H. Sarma

The online version contains supplementary material available at 10.1007/s40203-021-00100-2.

Herbal plants are often used as alternative medicine because they contain active compounds for the treatment of diseases and disorders with minimal side effects, and are easily obtained from the surrounding environment. Some of them have antiviral activity. This study aimed to analyze the potential of phytochemical compounds in the leaf of “pangi” (Pangium edule Reinw) as antiSARS-CoV-2 using molecular docking study. The drug- and lead-likeness properties of the selected compounds were obtained from the Swiss ADME and admetSAR online server tools. Molecular dynamics (MD) simulation of the selected ligand was carried out to validate the stability of the interaction. The results suggested that pangi leaves contain three compounds with remarkable binding affinities with Mpro (main protease) and RBD (receptor binding domain) were (5.beta.) pregnane-3,20.beta.-diol, 14.alpha.,18.alpha.-[4-methyl-3-oxo-(1-oxa-4-azabutane-1,4-diyl)]-, diacetate (PD), ethyl cholate (EC), and bis(3,5,5-trimethylhexyl) phthalate. Because EC will be metabolized in the body into cholic acid (Cho), this compound was then docked and validated using MD simulation. The compound has the best free binding energy (ΔG) with SARS-CoV-2 (–7.1 kcal/ mol with Mpro and –6.0 kcal/mol with RBD). Moreover, the compound is bound strongly to the active cavity of Mpro on Thr24, Thr26, His41, and Cys145 residues. The MM-GBSA calculation showed that the interaction of Cho with Mpro was higher than with RBD. According to the RMSD (root mean square deviation), RMSF (root mean square fluctuation), the radius of gyration (Rg), and intermolecular hydrogen bond (H-bond) analysis obtained from 50 ns MD simulations, Cho formed stable interactions with Mpro and RBD. The finding of this study indicated that Cho showed good anti-SARS-CoV-2 activity. The potential of the compound to inhibit the virus can serve as a starting point in the process of developing COVID-19 therapeutic natural medicine.

Objectives: Coronavirus disease 2019 (COVID-19) has had a global impact and is spreading quickly. ChuanKeZhi injection (CKZI) is widely used in asthma patients. In this paper, we aimed to explore active compounds of CKZ and determine potential mechanisms against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through network pharmacology, molecular docking and dynamic simulation studies. Materials and Methods: We used the Systematic Pharmacology Database and Analysis Platform of Traditional Chinese Medicine (TCMSP) to screen active compounds and potential target proteins of CKZ. COVID-19 target genes were screened via the American National Center for Biotechnology Information (NCBI) gene database and human gene database (GeenCards). The protein interaction network was constructed by the Protein Interaction Network Database (Search Tool for the Retrieval of Interacting Genes/Proteins (STRING)) platform. GO enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by the Metascape database. The main active compounds of CKZ were docked with angiotensin-converting enzyme 2 (ACE2), spike protein S1, and SARS-CoV-2-3CL pro and also docked with hub targets. We performed molecular dynamics (MD) simulation studies for validation. Results: We finally obtained 207 CKZ potential targets and 4681 potential COVID-19 targets. Key targets included mainly AKT1, TNF, IL6, VEGFA, IL1B, TP53, JUN, CASP3, etc. There were 217 Gene Ontology (GO) items in the GO enrichment analysis ( p < 0.05). The main KEGG pathways included the advanced glycation end products (AGE)- receptor for AGE (RAGE) signalling pathway in diabetic complications, rheumatoid arthritis, chemical carcinogenesis-receptor activation, alcoholic liver disease, etc. Molecular docking and dynamics simulation studies both exhibited great binding capacity. Conclusions: Network pharmacology, molecular docking and dynamics simulation studies were used to identify the potential and key targets, pharmacological functions, and therapeutic mechanisms of CKZI in the treatment of COVID-19. CKZI may be an effective and safe drug in COVID-19 treatment. However, further work is needed for validation.

B-cell lymphoma-extra large (Bcl-xL) can inhibit apoptosis via heterodimerization with pro-apoptotic Bcl-2 family proteins, and is over-expressed in many different types of human tumors and has been regarded as a novel cancer therapeutic strategy. Due to the fact that current Bcl-xl inhibitors lack sustained effectiveness and the occurrence of some unpredictable side effects, the development of new inhibitors is necessary. In this study, computational study was applied to a series of Bcl-xL inhibitors to reveal the relationship between structure and activities through applying molecular docking, three-dimensional qualitative structure-activity relationship (3D-QSAR), and molecular dynamic (MD) simulations. A molecular docking study was performed to explore possible modes of action between inhibitors and Bcl-xL protein. Subsequently, 3D-QSAR models were generated with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For the best CoMFA model, the Q2 and R2 values were computed as 0.927 and 0.999, while those were computed as 0.943 and 0.998 for the best CoMSIA model. Twenty new Bcl-xL inhibitors were designed, and all their predictive activities were improved than molecules in the dataset based on the contour maps. In addition, MD simulations were conducted to evaluate the stability of the complexes conformed by two inhibitors and Bcl-xL, and the results were consistent with those of the molecular docking and 3D-QSAR studies. Finally, binding free energy was computed through molecular mechanics performed by surface area approach (MM-GBSA), and the result congruent with the activities which indicated van der Waals as well as lipophilic energy contributing the most during the molecular with Bcl-xL protein binding. In brief, our research provided valuable information for further development of Bcl-xL inhibitors.

Presently, antimicrobial resistance is a major and worldwide concern due to high rate of mutation in microorganisms, widespread use, lack of efficacy of drugs, and low drug discovery rate. Considering the importance of N-heterocycles as antibiotics, perimidine derivatives 3(a–v) have been synthesized via cyclocondensation reaction of 1,8-diaminonaphthalene and aryl aldehydes. Further, the synthesized perimidines 3(a–v) were screened as potent antimicrobial agents via in-vitro, in-silico, ADME and MD simulation studies. All 22 derivatives 3(a–v) were studied against two-gram +ve (E. coli and P. aeruginosa), two-gram −ve (S. aureus and B. subtilis), and two fungal (A. niger and S. cerevisiae) strains using ciprofloxacin and fluconazole as reference drugs. The in-vitro study results showed that compounds 3e, 3h, 3l, and 3m were the most potent against S. aureus and 3(a–d), 3(g–i), and 3s were the most active against B. subtilis as compared to the standard. Furthermore, molecular docking studies were performed against Dihydrofolate reductase (PDB Id: 3SRW) from S. aureus, DNA gyrase (PDB Id: 4DUH) from E. coli, and ERG11 gene (PDB Id: 4LXJ). Compounds 3f, 3f/3m, and 3o were found to bind efficiently with the highest binding energy − 10.6, − 9.6, and − 11.3kcal/mol depicting the potential inhibitor of 3SRW, 4DUH, and 4LXJ receptor protein, respectively. The drug-likeness properties of compounds were studied using SwissADME program. To further validate these findings, molecular dynamics simulations were conducted to evaluate their binding stability. From simulation studies, it was observed that all the shortlisted compounds displayed stable binding within the active site of the selected proteins.Graphical abstract

To predict and characterize the three-dimensional (3D) structure of protein arginine methyltransferase 2 (PRMT2) using homology modeling, besides, the identification of potent inhibitors for enhanced comprehension of the biological function of this protein arginine methyltransferase (PRMT) family protein in carcinogenesis. An in silico method was employed to predict and characterize the three-dimensional structure. The bulk of PRMTs in the PDB shares just a structurally conserved catalytic core domain. Consequently, it was determined that ligand compounds may be the source of co-crystallized complexes containing additional PRMTs. Possible PRMT2 inhibitor compounds are found by using S-adenosyl methionine (SAM), a methyl group donor, as a positive control. Protein arginine methyltransferases are associated with a range of physiological processes, including as splicing, proliferation, regulation of the cell cycle, differentiation, and signaling of DNA damage. These functional capacities are also related to carcinogenesis and metastasis-several forms of PRMT have been cited in the literature. These include PRMT-1, PRMT-2, and PRMT-5. Among these, the role of PRMT-2 has been shown in breast cancer and hepatocellular carcinoma. To gain more insights into the role of PRMT2 in cancer pathogenesis, we opted to characterize tertiary structure utilizing an in silico approach. The majority of PRMTs in the PDB have a structurally conserved catalytic core domain. Thus, ligand compounds were identified as a possible source of co-crystallized complexes of other PRMTs. The SAM, a methyl group donor, is used as a positive control in order to identify potential inhibitor compounds of PRMT2 by the virtual screening method. We hypothesized that an inhibitor for other PRMTs could alter PRMT2 activities. Out of 45 inhibitor compounds, we ultimately identified three potential inhibitor compounds based on the results of the pharmacokinetics and binding affinity studies. These compounds are identified as 3BQ (PubChem CID: 77620540), 6DX (PubChem CID: 124222721), and TDU (PubChem CID: 53346504). Their binding affinities are -8.5 kcal/mol, -8.1 kcal/mol, and -8.8 kcal/mol, respectively. These compounds will be further investigated to determine the binding stability and compactness using molecular dynamics simulations on a 100 ns time scale. In vitro and in vivo studies may be conducted with these three compounds, and we think that focusing on them might lead to the creation of a PRMT2 inhibitor. Three strong inhibitory compounds that were non-carcinogenic also have drug-like properties. By using desirable parameters in root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), molecular surface area (MolSA), and intermolecular hydrogen bonding, complexes verified structural stability and compactness over the 100 ns time frame. Hossen MS, Islam MN, Pramanik MEA et al. Molecular Characterization and Potential Inhibitors Prediction of Protein Arginine Methyltransferase-2 (PRMT2) in Carcinoma: An Insight from Molecular Docking, ADMET Profiling and Molecular Dynamics Simulation Studies. Euroasian J Hepato-Gastroenterol 2024;14(2):160-171.

Medicinal herbs are being investigated for medicationhg development against SARS-CoV-2 as a rich source of bioactive chemicals. One of the finest approaches for finding therapeutically effective drug molecules in real time is virtual screening scheme such as molecular docking in conjunction with molecular dynamics (MD) simulation. These virtual techniques provide an ample opportunity for the screening of plausible inhibitors of SARS-CoV-2 different target proteins from a comprehensive and extensive phytochemical library. The study was designed to identify potential phytochemicals by virtual screening against different receptor proteins. In the current study, a library of plant secondary metabolites was created by manually curating 120 phytochemicals known to have antimicrobial as well as antiviral properties. In the current study, different potential phytochemicals were identified by virtual screening against various selected receptor proteins (i.e., viral main proteases, RNA-dependent RNA polymerase (RdRp), ADP ribose phosphatase, nonstructural proteins NSP7, NSP8, and NSP9) which are key proteins responsible for transcription, replication and maturation of SARS-CoV-2 in the host. Top three phytochemicals were selected against each viral receptor protein based on their best S-scores, RMSD values, molecular interactions, binding patterns and drug-likeness properties. The results of molecular docking study revealed that phytochemicals (i.e., baicalin, betaxanthin, epigallocatechin, fomecin A, gallic acid, hortensin, ichangin, kaempferol, limonoic acid, myricetin hexaacetat, pedalitin, quercetin, quercitrin, and silvestrol) have strong antiviral potential against SARS-CoV-2. Additionally, the reported preeminent reliable phytochemicals also revealed toxicity by no means during the evaluation through ADMET profiling. Moreover, the MD simulation study also exhibited thermal stability and stable binding affinity of the pedalitin with SARS-CoV-2 RdRp and SARS-CoV-2 main protease which suggests appreciable efficacy of the lead optimization. The biological activity and pharmacologically distinguishing characteristics of these lead compounds also satisfied as repurposing antiviral drug contenders and are worth substantial evaluation in the biological laboratory for the recommendation of being plausible antiviral drug candidates against SARS-CoV-2.

Main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2 the new strain of coronavirus. In this study, we evaluated biologically active compounds present in medicinal plants as potential SARS-CoV-2 Mpro inhibitors, using a molecular docking study with Autodock Vina software. Top seven compounds Afzelin, Phloroglucinol, Myricetin-3-O- rutinosid Tricin 7-neohesperidoside, Silybin, Kaempferol and Silychristin among 50 molecules of natural Origin (Algerian Medicinal plants) were selected which had better and significantly low binding energy as compared to the reference molecule with binding affinities of −9.3, −9.3, −9, −8.9, −8.5, 8.3 and −8.3 kcal mol−1 respectively. Then, we analyzed the ADME properties of the best 7 ligands using the Web server SwissADME. Two of small molecules have been shown to be the ideal candidates for further drug development. Finally, the stability of the both compounds complexed with Mpro was validated through molecular dynamics (MD) simulation, they displayed stable trajectory (RMSD, RMSF) and molecular properties with consistent interaction profile in molecular dynamics simulations, moreover, Silybin could form more stable complex with Mpro than Silychristin. Communicated by Ramaswamy H. Sarma