Abstract

The drug resistance in malarial parasites is increasingly emerging, hence it is essential to discover and develop alternative anti-malarial agents against both new and established drug targets. One of such possible drug targets is thiamine phosphate synthase because of its role and essentialness in the thiamine biosynthesis pathway. The present study aims to model the three-dimensional (3D) structure of thiamine phosphate synthase and to predict the potential inhibitors to derive therapeutic objectives for Plasmodium falciparum. The 3D structure was constructed using SWISS-MODEL and several computer-aided approaches were used for screening of drug-like compounds. In PyRx 0.8, molecular docking was conducted using AutoDock Vina. The absorption, distribution, metabolism and excretion properties were predicted using admetSAR. Post-docking results were analyzed using LigPlot+ program. The 3D model of thiamine phosphate synthase was generated using thiamine phosphate pyrophosphorylase from Pyrococcus furiosus as a template. Out of 156 compounds screened, only those 98 compounds which followed the Lipinski’s rule of five were used for molecular docking. The best 25 docked ligands were further subjected to admetSAR for evaluation of absorption, distribution, metabolism, excretion and toxicity properties. Among these, 3 compounds, 5b (ZINC000003953801), 5m (ZINC000001686969), and 5u (ZINC000002036738) showed good absorption, distribution, metabolism, excretion and toxicity properties. Impact of 14 nsSNPs on the PfThiE protein structure or function was also investigated. The predicted inhibitors in this study may be further oriented to the development of treatment through experimental therapeutic methods to suppress pathogenic action of P. falciparum.