Repurposing FDA-Approved Drugs for Eumycetoma Treatment: Homology Modeling and Computational Screening of CYP51 Inhibitors

Eumycetoma, a chronic fungal infection caused by Madurella mycetomatis, is a
neglected tropical disease characterized by tumor-like growths that can lead to permanent
disability and deformities if untreated. Predominantly affecting regions in Africa, South
America, and Asia, it imposes significant physical, social, and economic burdens. Current
treatments, including antifungal drugs like itraconazole, often show variable efficacy,
with severe cases necessitating surgical intervention or amputation. Drug discovery for
eumycetoma faces challenges due to limited understanding of the disease’s molecular
mechanisms and the lack of 3D structures for key targets such as Madurella mycetomatis
CYP51, a well-known target for azoles’ antifungal agents. To address these challenges,
this study employed computational approaches, including homology modeling, virtual
screening, free energy calculations, and molecular dynamics simulations, to repurpose
FDA-approved drugs as potential treatments for eumycetoma targeting Madurella mycetomatis CYP51. To this end, a library of 2619 FDA-approved drugs was screened, identifying three promising candidates: montelukast, vilanterol, and lidoflazine. These compounds demonstrated favorable binding affinities, strong interactions with critical residues of the homology model of Madurella mycetomatis CYP51, and stability in molecular
dynamics simulations, offering potential for further investigation as effective therapeutic
options for eumycetoma.