In-Silico Evaluation of Marine Natural Products as Potential Inhibitors of Sterol 14α-Demethylases (CYP51): Drug Target for Chagas Disease

Abstract

An in-silico integrated approach was used to screen marine natural products as potential inhibitors of enzyme sterol 14α-demethylase (CYP51) of Trypanosoma cruzi. From a library of 49,367 CMNPD compounds, 239 ligands with SP docking scores < −9.75 kcal/mol were filtered. These compounds are further refined using XP docking parameters, and 188 high-affinity inhibitors were shortlisted with docking scores ranging from −15.42 to −9.52 kcal/mol. MM-GBSA binding free energies of these protein ligand complexes ranged from −152.95 to −51.81 kcal/mol, and the top 30 complexes with ΔG_bind < −115.98 kcal/mol were selected for further study. ADMET analysis revealed four promising compounds—CMNPD21020, CMNPD34612, CMNPD10891, and CMNPD34622—with high binding affinity (ΔG_bind −135.00 to −119.20 kcal/mol), good permeability, optimal lipophilicity, and low predicted cardiotoxicity and CNS activity. These results indicate the potential of marine compounds.