{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T15:38:25Z","timestamp":1776440305195,"version":"3.51.2"},"reference-count":66,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,11]],"date-time":"2025-05-11T00:00:00Z","timestamp":1746921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Graduate Studies and Scientific Research at Jouf University","award":["DGSSR-2024-01-02065"],"award-info":[{"award-number":["DGSSR-2024-01-02065"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The increasing threat of antibiotic resistance and the declining efficiency of traditional drug discovery pipelines highlight the urgent need for novel drug targets and effective enzyme inhibitors against infectious diseases. Oligopeptidase B (OPB), a serine protease with trypsin-like specificity that processes low-molecular-weight peptides and oligopeptides, is present in bacteria and certain parasites but absent in mammals. This unique distribution makes OPB an attractive and selective target for antimicrobial drug development. Methods: Three-dimensional models of OPB from Serratia marcescens and Stenotrophomonas maltophilia, previously identified by our research group, were constructed via homology modeling using the best available OPB template from the RCSB Protein Data Bank. The S. marcescens OPB model was subjected to high-throughput virtual screening (HTVS) against the Natural Products Atlas (npatlas) database. Top-ranking compounds were further evaluated using Glide standard precision (SP) and extra precision (XP) docking protocols. Binding affinities were refined using molecular mechanics with generalized born and surface area (MM\u2013GBSA) calculations. Molecular dynamics (MD) simulations assessed binding stability, while absorption distribution metabolism excretion and toxicity (ADMET) profiling evaluated drug-likeness and pharmacokinetic properties. Results: Ten natural product compounds demonstrated stronger binding affinities than antipain, a well-known oligopeptide-based protease inhibitor, as indicated by their more favorable MM\u2013GBSA scores of \u221260.90 kcal\/mol (S. marcescens) and \u221227.07 kcal\/mol (S. maltophilia). Among these, dichrysobactin and validamycin E consistently exhibited favorable binding profiles across both OPB models. MD simulations confirmed the stability of their interactions with OPB active sites, maintaining favorable binding conformations throughout the simulation period. ADMET analysis suggested that while both compounds show promise, lead optimization is required to enhance their drug-like characteristics. Conclusions: This study identifies dichrysobactin and validamycin E as promising OPB inhibitors with potential antimicrobial activity. These findings support their further development as selective and potent agents against bacterial pathogens, including resistant strains, and underscore the need for experimental validation to confirm their efficacy and safety.<\/jats:p>","DOI":"10.3390\/ph18050709","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T03:59:26Z","timestamp":1747108766000},"page":"709","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of Bacterial Oligopeptidase B Inhibitors from Microbial Natural Products: Molecular Insights, Docking Studies, MD Simulations, and ADMET Predictions"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8751-4159","authenticated-orcid":false,"given":"Malik Suliman","family":"Mohamed","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3875-7968","authenticated-orcid":false,"given":"Tilal","family":"Elsaman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1981-6408","authenticated-orcid":false,"given":"Magdi Awadalla","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7108-3665","authenticated-orcid":false,"given":"Eyman Mohamed","family":"Eltayib","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8680-8427","authenticated-orcid":false,"given":"Abualgasim Elgaili","family":"Abdalla","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mona Timan","family":"Idriss","sequence":"additional","affiliation":[{"name":"Department of Nursing College, Northern Private College of Nursing, Arar 73312, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.bbi.2021.04.022","article-title":"Lifestyle risk factors and infectious disease mortality, including COVID-19, among middle aged and older adults: Evidence from a community-based cohort study in the United Kingdom","volume":"96","author":"Ahmadi","year":"2021","journal-title":"Brain Behav. 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