Structural analysis of Glucose-6-Phosphate Dehydrogenase (G6PD) variants from Northeast India and natural antioxidants as a pharmacological agent to alleviate G6PD deficiency associated challenges- An in silico approach

Abstract

The present study focuses on the structural deviation of four Glucose-6-phosphate dehydrogenase (G6PD) variants viz., Orissa, Kalyan-Kerala, Mahidol and A+ detected in Northeast Indian population and to assess the probable efficacy of natural antioxidants to combat G6PD deficiency associated challenges. G6PD deficiency caused by mutations in the g6pd gene, results in hemolysis of the Red Blood Corpuscles (RBCs) under oxidative stress. Over sixty years have passed since the identification of G6PD-associated enzymopathy; nonetheless, a treatment for the deficiency remains unavailable. Thus, the potential of natural antioxidants as a remedial agent against these variants were evaluated in silico. The three dimensional (3D) structures of the variants were modeled and validated. Molecular docking of variants with the natural antioxidants was performed using AutoDock Vina, wherein the binding affinities with G6PD Orissa, Kalyan-Kerala, Mahidol and A+ ranged between -5.2 to -9.2 kcal/mol, -5.1 to -9.8 kcal/mol, -5.2 to -9.4 kcal/mol and -5.0 to -10.5 kcal/mol, respectively. Drug-likeness and toxicity analyses were done using SwissADME and ProTox-II, respectively. Molecular dynamics simulation of the variants and the variant-antioxidant complexes done using GROMACS showed best fit in Orissa-Myricetin, Kalyan-Kerala-Apigenin, Mahidol-Catechin, and A+-Diadzen. Kalyan-Kerala-Apigenin was observed to have the least deviation compared to WT G6PD.