Molecular Mechanics with Generalized Born Surface Area (MMGBSA) Calculations and Docking Studies Unravel some Antimalarial Compounds Using Heme O Synthase as Therapeutic Target

Abstract

Abstract The enzyme Heme O Synthase (HOS) is essential for producing heme A and heme O, which are critical for defense against reactive oxygen species, drug detoxification, gas synthesis, transport, and electron transport in Plasmodium species . It has become vital to discover inhibitory molecules/compounds/medicines that target the synthesis of heme due to the emergence of drug‐resistant strains of Plasmodium falciparum . Therefore, in this study, we employed molecular mechanics with Generalized Born surface area (MMGBSA) calculations and docking studies to investigate potential antimalarial compounds targeting HOS from antimalarial botanicals. Screening these compounds, we have identified 2 compounds; Meliantrol and Tamarixetin with better binding affinities (−8.4 Kcal/mol and −8.3 Kcal/mol respectively) than the current standard inhibitor(Inabenfide) of HOS (−8.0 Kcal/mol). The MMGBSA calculations provided insight into the thermodynamics of the binding process and helped identify key interactions responsible for the stability of the HOS ‐ligand complex. In addition, the 2 compounds were further screened comparatively with the standard HOS inhibitor considering their protein‐ligand interaction profile and ADMET profile and these 2 selected compounds outperformed Inabenfide. Our results predict that these compounds are potential drug candidates with domiciled therapeutic functions against Malaria therefore, open doors for more experimental validations for drug development.