In silico pharmacology最新文献

{"title":"In-silico repurposing of antiviral compounds against Marburg virus: a computational drug discovery approach.","authors":"Rahul Kumar Singh, Kaushik Sarkar, Rajesh Kumar Das","doi":"10.1007/s40203-025-00323-7","DOIUrl":"10.1007/s40203-025-00323-7","url":null,"abstract":"<p><p>The Marburg virus (MARV), a member of the family Filoviridae, is a highly pathogenic virus causing severe hemorrhagic fever with extremely high mortality in humans and non-human primates. The MARV exhibits clinical and epidemiological features almost identical to those of the Ebola virus, no licensed vaccines or antiviral treatments have been developed yet for MARV. However, only a few treatments that remain uncertain of the disease are available to help bring a case for a new therapeutic approach. Considering the non-availability of any standard drug we have planned to identify potential inhibitors of VP24 (PDB ID: 4OR8) through a computational drug repurposing process. The workflow includes: identifying a druggable pocket on VP24, screening of FDA-approved antivirals via molecular docking, assessing the stability using molecular dynamics simulations, and estimating binding affinity through MM-PBSA calculations. After going through the analysis, the compound Bictegravir manifests as a hit compound which will undergo in vitro and in vivo validation to confirm its efficacy against MARV.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00323-7.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"41"},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network pharmacology and molecular docking to reveal the pharmacological mechanisms of <i>Abelmoschus esculentus</i> (l.) moench in treating breast cancer.","authors":"Ifeanyi Edozie Otuokere, Julian Ibeji Iheanyichukwu, Onuchi Marygem Mac-Kalunta, Chinedum Ifeanyi Nwankwo, Comfort Michael Ngwu, Stella Mbanyeaku Ufearoh, Brendan Chidozie Asogwa, Henry Chibueze Osiagor, Felix Chigozie Nwadire","doi":"10.1007/s40203-025-00329-1","DOIUrl":"10.1007/s40203-025-00329-1","url":null,"abstract":"<p><p>Breast cancer (BCa) is a major global health issue, impacting millions of women globally. A variety of synthetic medications exist for BRCA treatment; however, many of them have elevated risks of side effects and long-term therapy complications. Traditional formulations are gaining popularity as they resolve certain difficulties. This study utilises network pharmacology (NP) and molecular docking to elucidate the pharmacological processes of <i>Abelmoschus esculentus</i> (L.) Moench (AE) in the treatment of BCa. The phytoconstituents of AE were sourced from published literature and different databases. Lipinski's rule of five served as the standard for pharmacokinetic features, specifically focusing on compounds that adhere to Lipinski's criterion. Potential AE compound targets were obtained from SwissTargetPrediction. The GeneCard database was used for the BCa targets. The PPI of 183 common genes was evaluated using the STRING database. The GO and KEGG pathway analysis was conducted utilising the ShinyGO database. Docking studies were performed using PyRx virtual screening software. Molecular dynamics (MD) was performed using the Schrodinger suite. The Venn diagram illustrated 183 shared targets identified between the drugs and BCa. The 10 principal hub genes found are AKT1, HSP90AA1, PARP1, EGFR, ESR1, HIF1A, EP300, JUN, MAPK3, and MMP9. Analyses of protein-protein interactions (PPI), Gene Ontology (GO), and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment identified major biological processes and pathways implicated in cancer development. Docking has demonstrated robust interactions and may provide a strategy for suppressing BCa. MD results implied stability of the complex. The integrative approach elucidated not only the pharmacological property of AE in action against BCa but also laid a theoretical foundation for subsequent experimental verifications. This indeed helped further the development of novel therapeutic strategies using natural compounds for BCa treatment.</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"40"},"PeriodicalIF":0.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming aminoglycoside antibiotic resistance in <i>Mycobacterium tuberculosis</i> by targeting Eis protein.","authors":"Geethu S Kumar, Kuldeep Sharma, Richa Mishra, Esam Ibraheem Azhar, Vivek Dhar Dwivedi, Sharad Agrawal","doi":"10.1007/s40203-025-00325-5","DOIUrl":"10.1007/s40203-025-00325-5","url":null,"abstract":"<p><p>Tuberculosis (TB), a major global health concern, even after significant advancements in diagnosis and treatment, causing millions of deaths annually and severely impacting the healthcare systems of developing nations. Moreover, the rise of drug-resistant strains further diminishes the efforts made to control the infection and to overcome this scenario, highly effective drugs are required. Identifying new therapeutic uses of existing drugs through drug repurposing can significantly shorten the time and cost. In the current study, using a computational experimental approach, near about 3104 FDA-approved drugs and active pharmaceutical ingredients from Selleckchem database were screened against Enhanced intracellular survival (Eis) protein, responsible for causing drug resistance by inhibiting the aminoglycoside drug activity. Based on the three-level screening and Molecular Mechanics generalized Born surface area (MM/GBSA) scores, five drugs including Isavuconazonium sulfate, Cefotiam Hexetil Hydrochloride, Enzastaurin (LY317615), Salbutamol sulfate (Albuterol), and Osimertinib (AZD9291) were considered as potential Eis inhibitors. The 500 ns MD simulation results revealed that all these Eis-drug complexes are stable, with minor structural arrangements and stable binding patterns. The PCA and FEL analysis also confirmed the structural stability of the complexes. Overall, these drugs displayed promising results as Eis inhibitors, that can be regarded as suitable candidates for experimental validation.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"36"},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-silico structural and functional analysis of nonsynonymous single nucleotide polymorphisms in human <i>FOLH1</i> gene.","authors":"Abtin Tondar, Muhammad Irfan, Sergio Sánchez-Herrero, Hafsa Athar, Aleena Haqqi, Asim Kumar Bepari, Laura Calvet Liñán, David Hervás Marin","doi":"10.1007/s40203-025-00319-3","DOIUrl":"10.1007/s40203-025-00319-3","url":null,"abstract":"<p><p>Non-synonymous single nucleotide polymorphisms (nsSNPs), also known as missense SNPs, can seriously affect an individual's vulnerability to numerous diseases, including cancer. In this study, we conducted a comprehensive in-silico analysis to examine the structural and functional implications of nsSNPs within the Folate Hydrolase 1(<i>FOLH1</i>) gene, which encodes the Prostate-Specific Membrane Antigen (PSMA). A total of 504 SNPs were retrieved, and after filtering, 15 pathogenic nsSNPs were identified using five different in-silico tools. Three of these SNPs-R255H (rs375565491), R255C (rs201789325), and G168E (rs267602926)-were consistently predicted to be pathogenic across all in-silico tools. MutPred2 was used to predict the structural and functional consequences of the identified mutations. The analysis revealed multiple alterations in the PSMA protein, including changes in helical conformations, glycosylation patterns, transmembrane properties, and solvent accessibility. Furthermore, I-Mutant 2.0 analysis demonstrated a decrease in protein stability for most nsSNPs, except for rs267602926 (G168E), which was predicted to increase stability. Conservation analysis using ConSurf revealed varying degrees of amino acid conservation, with R255H and R255C identified as highly conserved residues, indicating their potential functional and structural significance. Additionally, post-translational modification (PTM) analysis indicated that while phosphorylation and methylation sites remained unchanged, specific glycosylation sites were lost in two pathogenic mutant variants (R255H and R255C), potentially affecting PSMA function and adversely impacting prostate cancer. Our findings highlight the importance of in silico studies to investigate the structural and functional impacts of <i>FOLH1</i> nsSNPs on the PSMA protein. Such in silico studies can deepen our understanding of the roles of nsSNPs in prostate cancer onset, progression, and drug resistance.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00319-3.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"32"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-silico development of a novel TLR2-mediating multi-epitope vaccine against <i>Mycobacterium tuberculosis</i>.","authors":"Swati Singh, Priyanshu Verma, Madhav Gaur, Lavi Bhati, Riya Madan, Prem P Sharma, Ayushi Rawat, Brijesh Rathi, Medha Singh","doi":"10.1007/s40203-025-00322-8","DOIUrl":"10.1007/s40203-025-00322-8","url":null,"abstract":"<p><p>Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (Mtb), still remains one of the leading causes of mortality worldwide. The elusive nature of this pathogen and its ability to develop drug resistance makes it a serious threat to global health. BCG, the only preventive vaccine for TB, has a limited efficacy and provides partial protection against the disease. A new effective recombinant vaccine capable of producing a stronger and more comprehensive immune response is required to address this global threat. In the present study, we adopted an in-silico approach to develop a multi-epitope vaccine by screening 198 \"regulatory proteins\" of Mtb H37Rv strain. Epitopes generated from these proteins were screened on the basis of antigenicity, cytokine profile, allergenicity, toxicity, conservancy and population coverage. Selected epitopes were docked with predominant MHC alleles that were used to develop a vaccine construct using suitable linkers and adjuvant. The construct was subjected to homology modelling, tertiary structure validation and refinement and was eventually docked with Toll-like receptor 2 receptor. Molecular dynamic simulation studies revealed stable interactions between the vaccine construct and TLR-2 receptor. The construct also displayed a high probability to elicit a protective immune response involving both humoral and cell-mediated components. In conclusion, the findings suggest that the constructed vaccine has the potential to induce a robust immune response against Mtb. However, further in-vitro and in-vivo studies are required to assess the safety, efficacy, and long-term protective effects of the vaccine construct.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00322-8.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"34"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computer-aided drug repurposing & discovery for Hepatitis B capsid protein.","authors":"Alireza Mohebbi, Seyed Pooria Tadayon Nabavi, Malihe Naderi, Kimia Sharifian, Farzane Behnezhad, Maryam Mohebbi, Amytis Gholami, Fatemeh Sana Askari, Azam Mirarab, Seyed Hamidreza Monavari","doi":"10.1007/s40203-025-00314-8","DOIUrl":"10.1007/s40203-025-00314-8","url":null,"abstract":"<p><p>The primary objective of this study is to harness computer-aided drug repurposing (CADR) techniques to identify existing FDA-approved drugs that can potentially disrupt the assembly of the Hepatitis B Virus (HBV) core protein (HBcAg), an essential process in the virus's life cycle. By targeting this critical step, our study aims to expand the repertoire of therapeutic options for managing chronic Hepatitis B infection, a major global health challenge. Utilizing a combination of computational methods, including the CavityPlus server for ability to analyze druggable protein cavities and extract pharmacophore features and LigandScout for pharmacophore-based virtual screening of a vast library of FDA-approved drugs was conducted. Molecular dynamic simulation (MDS) was employed to evaluate the stability of HBcAg, complexed with Heteroaryldihydropyrimidine (HAP) and statins exhibiting particularly strong binding energies and conformational compatibility. Our approach focused on identifying pharmacophore features that align with known HBcAg inhibitors. The study identified several promising candidates, including Ciclopirox olamine, Voriconazole, Enasidenib, and statins, demonstrating potential interactions with HBc protein residues. Molecular docking further validated these interactions. The significance of these findings lies in their potential to offer new, effective therapeutic strategies for HBV treatment, particularly as alternatives to current therapies that often suffer from issues of viral resistance and adverse side effects. MDS analysis verified the robustness of HAP and statins by showing a high level of binding energies and compatibility with HBcAg. Our results provide a foundation for further experimental validation and underscore the utility of computer-aided drug repurposing as a rapid, cost-effective approach to drug discovery in antiviral research. This study contributes to our understanding of HBV biology and opens avenues for developing novel anti-HBV therapies based on repurposed drugs. The highlighted compound may also enhance the challenges of drug resistance when used as a combination therapy.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"35"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virtual perspectives of sanguinarine on cancer prevention and treatment through molecular dynamic study.","authors":"Vikas Sharma, Arti Gupta, Anshul Singh, Shivani Tyagi, Hrithika Panday, Saurabh Srivastava, Sathvik Belagodu Sridhar, Safia Obaidur Rab, Sandeep Kumar Shukla","doi":"10.1007/s40203-025-00315-7","DOIUrl":"10.1007/s40203-025-00315-7","url":null,"abstract":"<p><p>Cancer prevention involves resisting cancer development at initial stages, retarding angiogenesis and initiating cancer cell apoptosis. Through the use of virtual screening, binding free energy calculations, and molecular dynamics simulations, we were able to identify compounds with potential anticancer activity.\"During the virtual screening process, compounds with promising drug-like properties were chosen using the Lipinski rule of five, and their binding affinities were evaluated by docking studies. In-silico activity of six different phytochemicals against established cancer specific proteins (NF-kB, p53, VEGF, BAX/BCl-2, TNF-alpha) were performed out of which p53, VEGF, BCl-2 has shown significant results. Sanguinarine has shown good docking score of -9.0 with VEGF and - 8.8 with Bcl-2 receptor and has been selected for molecular dynamics simulation. The results of Molecular Dynamics Simulations (MD) studies showed that RMSD and RMSF values of sanguinarine within an acceptable global minima (3-5.5 Å) for p53, VEGF, BAX/BCl-2. The computational models employed in this study produced important insights into the molecular mechanisms via which Sanguinarine prevents cancer by acting against p53, VEGF, and BCl-2 and by blocking the angiogenic, apoptotic, and proliferative pathways involved in the formation of cancer. The results suggest that the pharmacological activity of the selected phytomolecule (sanguinarine) is a promising avenue for cancer prevention.</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"33"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11861490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143525617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular modeling of the interactions of compounds of <i>Irvinga wombulu</i> against dihydrofolate reductase-thymidylate synthase in <i>Plasmodium falciparum</i> towards development of anti-malarial drug.","authors":"Amarachi Chike-Ekwughe, Hassan Taiye Abdulameed, Grace I Adebayo-Gege, Abubakar Usman, Emmanuel Joy Omoyungbo, Adeola Adefoluke Ala, Abayomi Emmanuel Adegboyega, Titilayo Omolara Johnson","doi":"10.1007/s40203-025-00317-5","DOIUrl":"10.1007/s40203-025-00317-5","url":null,"abstract":"<p><p>Malaria is a significant global health burden that affects the majority of people in the world. Nigeria still accounts for the highest percentage of the worldwide malaria burden, with 27% of estimated malaria cases and 31% of estimated deaths due to malaria in 2022. While antimalarial effects have been attributed to some active compounds from medicinal plants, no study has been conducted on <i>Irvingia wombulu</i> (IW). Therefore, this study aimed to evaluate the in silico antimalarial activity of some active compounds identified after gas chromatography/mass spectrometry (GC/MS) studies on Irvingia wombolu. The compounds were docked against the anti-malaria target Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) of Plasmodium falciparum with PDB ID 3QGT and their pharmacokinetic properties were also predicted. This was followed by a molecular dynamics (MD) simulation of the protein in complex with the most promising IW compound. The GC-MS result revealed 44 phytoconstituents from IW. The Docking analysis revealed the following best binding energies (kcal/mol): alpha-tocopherol-beta-D-mannoside (-11.289), gamma-tocopherol (- 7.308), and linolenic acid (- 6.822). MD Simulation showed that the selected compound exhibited a stable conformation in the active site of the flexible protein. Pharmacokinetics analysis suggested that the compounds will be orally bio-available when administered. Therefore, these results indicate that these compounds can be considered for experimental validation and further development into antimalarial drugs.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"31"},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De novo in silico screening of natural products for antidiabetic drug discovery: ADMET profiling, molecular docking, and molecular dynamics simulations.","authors":"Sulyman Olalekan Ibrahim, Yusuf Oloruntoyin Ayipo, Halimat Yusuf Lukman, Fatimah Aluko Abubakar, Asiat Na'Allah, Rashidat Arije Katibi-Abdullahi, Marili Funmilayo Zubair, Olubunmi Atolani","doi":"10.1007/s40203-025-00320-w","DOIUrl":"10.1007/s40203-025-00320-w","url":null,"abstract":"<p><p>Epigenetic dysfunction which has implicated disease conditions such as diabetes highlights the urgency for the discovery of novel therapeutic alternatives. The rising global incidences of diabetes and the limitations of existing treatments further exacerbate the quest for novel antidiabetic agents' discovery. This study leverages computational approaches to screen selected bioactive natural product phytoconstituents for their potential anti-diabetic properties. Utilizing pharmaceutical profiling, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions, molecular docking, and molecular dynamics (MD) simulations, the drug-likeness and binding affinity of these natural compounds against human pancreatic amylase was investigated. Out of the total 24,316 ZINC compounds screened for their binding scores with amylase, ZINC85593620, ZINC85593668, and ZINC85490447 came top. The compounds had higher binding scores than the standards (acarbose and ranirestat) with ZINC85593620 having the highest docking score of - 12.162 kcal/mol and interacted with key amino acid residues such as TRP 59, ILE 148, and ASP 197. Further validation through MD simulations reveals that all the compounds showed minimal fluctuations relative to the standards indicating strong and stable binding interactions suggesting potential effective inhibition of the enzyme. ZINC85593620 and ZINC85593668 showed promising distribution and availability characteristics for amylase inhibition. Overall, the compounds displayed potential amylase inhibition which underscores their use as promising natural products in developing new antidiabetic drugs. Further experimental validations are recommended to offer a potential solution to the pressing need for safer and more effective antidiabetic therapies.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"29"},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Afobazole: a potential drug candidate which can inhibit SARS CoV-2 and mimicry of the human respiratory pacemaker protein.","authors":"Govinda Rao Dabburu, Anjali Garg, Neelja Singhal, Manish Kumar","doi":"10.1007/s40203-025-00316-6","DOIUrl":"10.1007/s40203-025-00316-6","url":null,"abstract":"<p><p>In COVID-19 patients, respiratory failure was reported due to damage to the respiratory centers of the brainstem. Molecular mimicry of three brainstem pre-Botzinger complex proteins (DAB1, AIFM and SURF1) was regarded as the underlying reason for respiratory failure and the autoimmune neurological sequelae. Of the three brainstem proteins mimicked by SARS CoV-2, corresponding sequences to two of the mimicry peptides were located in the N-protein of SARS CoV-2. N-protein is important for viral RNA synthesis and genome packaging. Here, we have used molecular modeling, docking and MD simulations to discern potential drugs which can inhibit molecular mimicry of DAB1 by SARS CoV-2 and also eliminate it by interfering in genome packaging. The binding site (drug target) for molecular docking was defined as the amino acid sequence extending from position 168-185 of the N-protein which was a SLiM region and also included the mimicry hexapeptide. Molecular docking after MD simulations was used to discern probable inhibitors of the drug-target from FDA-approved neurological drugs in the Broad Institute's Drug Repurposing Hub. Our results revealed that an anti-anxiety drug afobazole qualified the ADMET parameters, formed a stable complex with the drug-target and exhibited the highest binding energy (-88.21 kJ/mol). This suggests that afobazole can be repurposed against SARS CoV-2 for disrupting molecular mimicry of human DAB1 protein and also eliminate the etiopathological agent by interfering in viral genome packaging.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00316-6.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 1","pages":"30"},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}