Malaria Prophylactics Through Heat Shock Protein 70x Chaperone Inhibition by Alkaloids of <i>Polyalthia longifolia</i> : An <i>I</i> <i>n Silico</i> Investigation

Abstract Malaria has been a global health burden despite means of diagnosis, preventive, and therapeutic measures are well practiced. The major obstacles are resistance to drugs and insecticide resistance by the female anopheles mosquito. The search for an effective and safe antimalarial drug is of dire importance, and in this regard, phytochemicals‐based formulations from natural products were explored by computational approach. The heat‐shock protein 70x of Plasmodium falciparum ( Pf Hsp70x), responsible for the virulence and endothelial attachment to the host stands as a good druggable target. The capability of alkaloids present in Polyalthia longifolia in binding with the receptor was assessed by molecular docking calculations and six different molecules distinctly showed better docking scores (from −14.3 to −14.0 kcal/mol) than that of the native ligand (−9.4 kcal/mol). (R)‐3‐(3,4‐dimethoxyphenyl)‐6‐hydroxy‐7,8‐dimethoxy‐2‐methyl‐3,4‐dihydroisoquinolin‐1(2H)‐one (5AD) and (S)‐2,9,11‐trihydroxy‐3,10‐dimethoxy‐5,6,13,13a‐tetrahydro‐8H‐isoquinolino[3,2‐a]isoquinolin‐8‐one (5M) formed spatially and thermodynamically stable adducts with the receptor as determined from molecular dynamics simulations. The normal functioning of Pf Hsp70x could be halted and the treatment of the disease could be achieved. The hit molecules, 5AD and 5M showed druglike properties with good bioavailability along with safety features comparable with the reference drugs from in silico approach and are recommended for experimental verification.