Docking predictions based Plasmodium falciparum phosphoethanolamine methyl transferase inhibitor identification and in-vitro antimalarial activity analysis

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 ( Pf pmt) 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 (IC 50 ). Compounds ZINC02103914 and ZINC12882412 were found to have good druglike properties and affinity for Pf pmt also inhibited P. falciparum growth at very low µM IC 50 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 Pf pmt 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.

Antimalarial activity of Curcuma caesia against 3D7 and K1 strains of Plasmodium falciparum

“…But PMT from these organisms use multiple methyltransferase domains for the S-adenosylmethionine (AdoMet) reactions which is a three-step S-adenosylmethionine-dependent methylation of the nitrogen atom of phosphoethanolamine to phosphocholine. In P. falciparum, this enzymatic reaction is a limiting step in the pathway of synthesis of phosphatidylcholine from serine, hence it is potent new drug target for antimalarial drug discovery.and plays an important role in the development, replication and survival of the parasite within human red blood cells [11,25].…”

“…Hence, it is vital for survival and growth of Plasmodium falciparum. As this enzyme is absent in humans, so it's good drug target in search of new anti-malarial drug [11]. Fifty-three metabolites were obtained from a previous study [7] by GCMS analysis of methanol and ethyl acetate extract of Curcuma caesia were used as a ligand for docking study.…”

Computational and experimental elucidation of Plasmodium falciparum phosphoethanolamine methyltransferase inhibitors: Pivotal drug target

“…After 24 hrs incubation MTT 5mg/ml was added to the plate and 4 hrs incubation was given. The supernatant was removed and added with DMSO to each well and the readings of absorbance were recorded at 580nm using Synergy/HTX MultiScan reader (BioTek) [36–37]. The Lethal dose LD 50 of each primary hits were calculated as mean from experiments in triplicate.…”

Quantitative Structure Activity Relationship (QSAR) Investigations and Molecular Docking Analysis of Plasmodium Protein Farnesyltransferase Inhibitors as Potent Antimalarial Agents

“…Inhibitors of the protein farnesyltransferase (PFT) enzyme have emerged as a promising target for treating malaria caused by the Plasmodium falciparum parasite. Farnesyltransferase is a -316 -catalytic enzyme that catalyzes the transfer of a farnesyl residue from farnesyl diphosphate to the thiol of a cysteine side chain of proteins carrying the CAAX-tetra peptide sequence (C: cysteine, A: aliphatic amino acid, X: serine or methionine) at their C terminus [5,6]. PFT inhibitors are promising drugs for the treatment of malaria, and a number of different scaffolds have been shown to inhibit the growth of the malaria parasite in vitro and in vivo [7].…”