{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:04:23Z","timestamp":1791903863676,"version":"4.3.4"},"reference-count":111,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T00:00:00Z","timestamp":1745107200000},"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-2023-01-02550"],"award-info":[{"award-number":["DGSSR-2023-01-02550"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Eumycetoma, caused by Madurella mycetomatis, is a chronic fungal infection with limited treatment options and increasing drug resistance. CYP51, a key enzyme in ergosterol biosynthesis, is a well-established target for azole antifungals. However, existing azole drugs demonstrate limited efficacy in treating eumycetoma. Microbial-based natural products, with their structural diversity and bioactivity, offer a promising source for novel CYP51 inhibitors. This study aimed to identify potential Madurella mycetomatis CYP51 inhibitors from microbial natural products using molecular docking, MM-GBSA calculations, ADMET analysis, and molecular dynamics (MD) simulations. Methods: Virtual screening was conducted on a library of microbial-based natural products using an in-house homology model of Madurella mycetomatis CYP51, with itraconazole as the reference drug. The top compounds from initial docking were refined through Standard and Extra Precision docking. MM-GBSA calculations assessed binding affinities, and ADMET analysis evaluated drug-like properties. Compounds with favorable properties underwent MD simulations. Results: The computational investigations identified 34 compounds with better docking scores and binding affinity than itraconazole. Of these, 9 compounds interacted with the heme group and key residues in the active site of Madurella mycetomatis CYP51. In silico pharmacokinetic profiling identified 3 compounds as promising candidates, and MD simulations confirmed their potential as CYP51 inhibitors. Conclusions: The study highlights microbial-derived natural products, particularly monacyclinone G, H, and I, as promising candidates for Madurella mycetomatis CYP51 inhibition, with the potential for treating eumycetoma, requiring further experimental validation.<\/jats:p>","DOI":"10.3390\/ph18040598","type":"journal-article","created":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T20:31:36Z","timestamp":1745181096000},"page":"598","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Identification of Microbial-Based Natural Products as Potential CYP51 Inhibitors for Eumycetoma Treatment: Insights from Molecular Docking, MM-GBSA Calculations, ADMET Analysis, and Molecular Dynamics Simulations"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3875-7968","authenticated-orcid":false,"given":"Tilal","family":"Elsaman","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4172-4585","authenticated-orcid":false,"given":"Mohamed Khalid Alhaj","family":"Awadalla","sequence":"additional","affiliation":[{"name":"Pharmacy Program, Wad Medani College of Medical Sciences and Technology, Wad Medani 21111, Gezira, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8751-4159","authenticated-orcid":false,"given":"Malik Suliman","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"myae044","DOI":"10.1093\/mmy\/myae044","article-title":"Eumycetoma causative agents: A systematic review to inform the World Health Organization priority list of fungal pathogens","volume":"62","author":"Clark","year":"2024","journal-title":"Med. 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