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
Abstract
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…
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