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

<b>Background/Objectives:</b> Eumycetoma, caused by <i>Madurella mycetomatis</i>, 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 <i>Madurella mycetomatis</i> CYP51 inhibitors from microbial natural products using molecular docking, MM-GBSA calculations, ADMET analysis, and molecular dynamics (MD) simulations. <b>Methods:</b> Virtual screening was conducted on a library of microbial-based natural products using an in-house homology model of <i>Madurella mycetomatis</i> 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. <b>Results:</b> 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 <i>Madurella mycetomatis</i> CYP51. In silico pharmacokinetic profiling identified 3 compounds as promising candidates, and MD simulations confirmed their potential as CYP51 inhibitors. <b>Conclusions:</b> The study highlights microbial-derived natural products, particularly monacyclinone G, H, and I, as promising candidates for <i>Madurella mycetomatis</i> CYP51 inhibition, with the potential for treating eumycetoma, requiring further experimental validation.