ABSTRACT

Glutamate dehydrogenase is an NADP-dependent enzyme that plays a major role in maintaining a reduced state in plasmodia. Clinically effective chloroquine and mefloquine inhibit the enzyme glutamate dehydrogenase thus inhibits antioxidative enzymes like glutathione reductase and thioredoxin which induce oxidative stress. In a highly oxidized state, plasmodia fail to survive. Chloroquine and Mefloquine contain a quinoline scaffold to which the tertiary amine-containing side chain is attached. From these drug molecules as well as by the detailed study of the structure-activity relationship of quinolines, a series of molecules have been designed and developed by molecular docking. Among these all designed compounds, compound number 2(d)(-121.51 kcal/mol), 2(f)(-109.83 kcal/mol), 1(f)(-108.56 kcal/mol) and 1(d)(-103.18 kcal/mol) shows good binding affinity than other designed compounds. Molinspiration online software tool was used to predict bioavailability that shows all compounds are active on G- protein coupled receptor. SWISSADME program was used to study in silico toxicity, indicating all the compounds follow Lipinski rule of five and compounds 1(b), 1(d), 1(e), 1(f), 1(g), 2(b), 2(d), 2(e), 2(f), 2(g) do not penetrate the blood-brain barrier. The designed series of novel 1-Azetidinone substituted benzimidazole derivatives exhibit good binding affinity with Plasmodium Falciparum glutamate dehydrogenase. The performed study contributed a better perceptive of molecular modeling necessity for maintaining or improving Plasmodium Falciparum glutamate dehydrogenase inhibitors. Keywords: Glutathione reductase, Thioredoxin, NADP, Oxidative stress, iGEMDOCK, YASARA, SWISSADME, Molinspiration
Publication date: 01/10/2023

https://ijbpas.com/pdf/2023/October/MS_IJBPAS_2023_7450.pdf

Download PDF
https://doi.org/10.31032/IJBPAS/2023/12.10.7450