In silico study of FDA-approved drugs on Leishmania infantum CYP51, a drug repositioning approach in visceral leishmaniasis

Leishmaniasis is a neglected disease with an estimated 1 million new cases per year worldwide. Safer and more accessible treatments for this disease remain a priority in endemic countries given the severity of the adverse effects of current therapies, which include cardiotoxicity, hepatotoxicity, hypokalemia, nephrotoxicity, and shivering.¹ In this study, we focus on a drug repositioning strategy through molecular docking, the New Molecular Entities (NMEs) approved by the FDA from 2019 to date were used, which are active moieties that FDA had not previously approved, either as a single ingredient drug or as part of a combination product.² A crystal of sterol 14-alpha demethylase from Leishmania infantum (PDB: 3L4D) was used as a therapeutic target.³ This enzyme catalyzes the removal of the 14α-methyl group from sterol precursors, an essential reaction for membrane biogenesis and an excellent target for antileishmanial chemotherapy for a causative agent of visceral leishmaniasis.³ 16 of the 125 NMEs approved by the FDA demonstrated to have greater affinity than the co-crystallized inhibitor (fluconazole) of the target in a molecular docking performed with FRED software and to interact with the same residues as the co-crystallized inhibitor.^4,5 This method is a compelling option for identifying new uses for existing drugs, and a quick option to find safer treatments for leishmaniasis.