{"title":"猴痘病毒假定蛋白的功能特征和结构预测以及潜在抑制剂的鉴定。","authors":"Reana Raen, Muhammad Muinul Islam, Redwanul Islam, Md Rabiul Islam, Tanima Jarin","doi":"10.1007/s11030-024-10935-4","DOIUrl":null,"url":null,"abstract":"<p><p>The excessive activation of the monkeypox virus (MPXV-Congo_8-156) is linked to various skin and respiratory disorders such as rashes, fluid-filled blisters, swollen lymph nodes and encephalitis (inflammation of the brain), highlighting MPXV-Congo_8-156 as a promising target for drug intervention. Despite the effectiveness of Cidofovir, in inhibiting MPXV activity, its limited ability to penetrate the skin and its strong side effects restrict its application. To address this challenge, we screened 500 compounds capable of penetrating the skin and gastrointestinal tract to identify potent MPXV inhibitors. Various characterization schemes and structural models of MPXV-Congo_8-156 were explored with bioinformatics tools like PROTPARAM, SOPMA, SWISS-MODEL and PROCHECK. Using molecular docking in PyRx, we evaluated the binding affinities of these compounds with MPXV-Congo_8-156 and identified the top five candidates ranging from - 9.2 to - 8.8 kcal/mol. ADMET analysis indicated that all five compounds were safer alternatives, showing no AMES toxicity or carcinogenicity in toxicological assessments. Molecular dynamics (MD) simulations, conducted for 100 ns each, confirmed the docking interactions of the top five compounds alongside the control (Cidofovir), validating their potential as MPXV inhibitors. The compounds with PubChem CID numbers 4061636, 4422538, 3583576, 4856107 and 4800629 demonstrated strong support in terms of root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA) value, hydrogen bond analysis, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis. Thus, our investigation identified these five compounds as promising inhibitors of MPXV, offering potential therapeutic avenues. However, further in vivo studies are necessary to validate our findings.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Functional characterization and structural prediction of hypothetical proteins in monkeypox virus and identification of potential inhibitors.\",\"authors\":\"Reana Raen, Muhammad Muinul Islam, Redwanul Islam, Md Rabiul Islam, Tanima Jarin\",\"doi\":\"10.1007/s11030-024-10935-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The excessive activation of the monkeypox virus (MPXV-Congo_8-156) is linked to various skin and respiratory disorders such as rashes, fluid-filled blisters, swollen lymph nodes and encephalitis (inflammation of the brain), highlighting MPXV-Congo_8-156 as a promising target for drug intervention. Despite the effectiveness of Cidofovir, in inhibiting MPXV activity, its limited ability to penetrate the skin and its strong side effects restrict its application. To address this challenge, we screened 500 compounds capable of penetrating the skin and gastrointestinal tract to identify potent MPXV inhibitors. Various characterization schemes and structural models of MPXV-Congo_8-156 were explored with bioinformatics tools like PROTPARAM, SOPMA, SWISS-MODEL and PROCHECK. Using molecular docking in PyRx, we evaluated the binding affinities of these compounds with MPXV-Congo_8-156 and identified the top five candidates ranging from - 9.2 to - 8.8 kcal/mol. ADMET analysis indicated that all five compounds were safer alternatives, showing no AMES toxicity or carcinogenicity in toxicological assessments. Molecular dynamics (MD) simulations, conducted for 100 ns each, confirmed the docking interactions of the top five compounds alongside the control (Cidofovir), validating their potential as MPXV inhibitors. The compounds with PubChem CID numbers 4061636, 4422538, 3583576, 4856107 and 4800629 demonstrated strong support in terms of root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA) value, hydrogen bond analysis, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis. Thus, our investigation identified these five compounds as promising inhibitors of MPXV, offering potential therapeutic avenues. However, further in vivo studies are necessary to validate our findings.</p>\",\"PeriodicalId\":708,\"journal\":{\"name\":\"Molecular Diversity\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2024-07-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Diversity\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1007/s11030-024-10935-4\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-024-10935-4","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Functional characterization and structural prediction of hypothetical proteins in monkeypox virus and identification of potential inhibitors.
The excessive activation of the monkeypox virus (MPXV-Congo_8-156) is linked to various skin and respiratory disorders such as rashes, fluid-filled blisters, swollen lymph nodes and encephalitis (inflammation of the brain), highlighting MPXV-Congo_8-156 as a promising target for drug intervention. Despite the effectiveness of Cidofovir, in inhibiting MPXV activity, its limited ability to penetrate the skin and its strong side effects restrict its application. To address this challenge, we screened 500 compounds capable of penetrating the skin and gastrointestinal tract to identify potent MPXV inhibitors. Various characterization schemes and structural models of MPXV-Congo_8-156 were explored with bioinformatics tools like PROTPARAM, SOPMA, SWISS-MODEL and PROCHECK. Using molecular docking in PyRx, we evaluated the binding affinities of these compounds with MPXV-Congo_8-156 and identified the top five candidates ranging from - 9.2 to - 8.8 kcal/mol. ADMET analysis indicated that all five compounds were safer alternatives, showing no AMES toxicity or carcinogenicity in toxicological assessments. Molecular dynamics (MD) simulations, conducted for 100 ns each, confirmed the docking interactions of the top five compounds alongside the control (Cidofovir), validating their potential as MPXV inhibitors. The compounds with PubChem CID numbers 4061636, 4422538, 3583576, 4856107 and 4800629 demonstrated strong support in terms of root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA) value, hydrogen bond analysis, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis. Thus, our investigation identified these five compounds as promising inhibitors of MPXV, offering potential therapeutic avenues. However, further in vivo studies are necessary to validate our findings.
期刊介绍:
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;