Abstract
The increased multidrug resistance among antimalarial drugs produces the urgency of potent anti malarial to combat resistant malaria and the malaria burden worldwide. The protein which may prevent the growth or transmission of malaria parasite may be the great target for rational drug designing. Plasmodium falciparum phosphoethanolamine methyltransferase (Pfpmt) absent in human catalyzes triple methylation of ethanolamine into phosphocholine for phosphatidylcholine biosynthesis from serine decarboxylation phosphoethanolamine methyltransferase pathway for the membrane development at asexual as well as sexual stages of parasite. The Plasmodium requires production of membrane rapidly for growth and multiplication. Hence, the phosphoethanolamine methyltransferase of Plasmodium falciparum was selected as drug target for rational drug designing. Using Discovery studio 3.5 software the library of zinc compounds was screened against target and analyzed. The compounds with better druglike properties and docking affinity and binding interaction for target protein were procured for in vitro analysis against Plasmodium falciparum culture (IC50). Compounds ZINC02103914 and ZINC12882412 were found to have good druglike properties and affinity for Pfpmt also inhibited P. falciparum growth at very low µM IC50 concentration 3.0 µM and 2.1 µM respectively also found nontoxic in vitro against HEK-293 cells. Simulation study of best inhibitor revealed the specificity for the target protein. Hence, the compounds possessed the immense probability of being inhibitors of Pfpmt and may be optimized as antimalarial agent for combinational therapy to overcome the multidrug resistance and may also be used as template for optimization and rational drug designing.
Highlights
Malaria is a mosquito borne disease in humans caused by unicellular microorganism called parasitic Plasmodium protozoa
The compound library built from natural compound of zinc database was screened based on the docking, Lipinski rule of five and absorption distribution metabolism excretion and toxicity (ADMET) analysis
Compounds were selected based on the good docking scoring and ADMET physicochemical properties
Summary
Malaria is a mosquito borne disease in humans caused by unicellular microorganism called parasitic Plasmodium protozoa. Compounds showed interaction with crucial amino acids like residues Tyr19 and His132 which are important for formation of catalytic dyad and other tyrosine residues important for transmethylation of phosphoethanolamine. All selected compounds formed hydrogen bonds with crucial amino acids of pCholine binding pocket importantly, with Tyrosine residues.
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