Natural products for treatment of Plasmodium falciparum malaria: An integrated computational approach.

Malaria is a life-threatening infectious disease with an estimated 229 million cases in the year 2019 worldwide. Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase (PfDXR) is one of the key enzymes in the biosynthetic pathway of isoprenoid, (required for parasite growth and survival) and considered as an attractive target for designing anti-malarial drugs. Fosmidomycin is an effective DXR inhibitor and has been proven effective and safe against P. falciparum in clinical trials. However, due to low bioavailability and inappropriate drug attributes, it is not a preferred option. The present study was performed to identify PfDXR inhibitors with improved pharmacology/safety. For this purpose, an integrated computational framework, comprising of pharmacophore modeling, virtual screening, molecular docking, molecular dynamics (MD) simulation and MM/PBSA, was used. The binding free energy analysis was performed using a focused library of phytochemicals established from medicinal plants. The study identified four bioactive compounds namely, Myricetin 3-rhamnoside, 7-O-Galloyltricetiflavan, (25S)-5-beta-spirostan-3-beta-ol 3-O-beta-d-glucopyranosyl-(1->2)-beta-d-glucopyranoside, and Oleanolic acid 28-O-beta-d-glucopyranoside as potential inhibitors of PfDXR. The selection of these four compounds was based on pharmacophore mapping, docking score, binding stability, molecular interactions with the residues of PfDXR active site, binding stability and free energy estimation. In conclusion, medicinal plant-based scaffolds were predicted with enhanced efficacy and adequate physiochemical/pharmacokinetic profile that might be helpful in controlling malaria.