Metabolic pathway analysis and molecular docking analysis for identification of putative drug targets in Toxoplasma gondii: novel approach

Abstract

Toxoplasma gondii is an obligate intracellular apicomplexan parasite that can infect a wide range of warm-blooded animalsincluding humans. In humans and other intermediate hosts, toxoplasma develops into chronic infection that cannot be eliminated byhost’s immune response or by currently used drugs. In most cases, chronic infections are largely asymptomatic unless the hostbecomes immune compromised. Thus, toxoplasma is a global health problem and the situation has become more precarious due tothe advent of HIV infections and poor toleration of drugs used to treat toxoplasma infection, having severe side effects and alsoresistance have been developed to the current generation of drugs. The emergence of these drug resistant varieties of T. gondii hasled to a search for novel drug targets. We have performed a comparative analysis of metabolic pathways of the host Homo sapiensand the pathogen T. gondii. The enzymes in the unique pathways of T. gondii, which do not show similarity to any protein from thehost, represent attractive potential drug targets. We have listed out 11 such potential drug targets which are playing someimportant work in more than one pathway. Out of these, one important target is Glutamate dehydrogenase enzyme; it plays crucialpart in oxidation reduction, metabolic process and amino acid metabolic process. As this is also present in the targets of tropicaldiseases of TDR (Tropical disease related Drug) target database and no PDB and MODBASE 3D structural model is available,homology models for Glutamate dehydrogenase enzyme were generated using MODELLER9v6. The model was further exploredfor the molecular dynamics simulation study with GROMACS, virtual screening and docking studies with suitable inhibitorsagainst the NCI diversity subset molecules from ZINC database, by using AutoDock-Vina. The best ten docking solutions wereselected (ZINC01690699, ZINC17465979, ZINC17465983, ZINC18141294_03, ZINC05462670, ZINC01572309, ZINC18055497_01,ZINC18141294, ZINC05462674 and ZINC13152284_01). Further the Complexes were analyzed through LIGPLOT. On the basis ofComplex scoring and binding ability it is deciphered that these NCI diversity set II compounds, specifically ZINC01690699 (as ithas minimum energy score and one of the highest number of interactions with the active site residue), could be promisinginhibitors for T. gondii using Glutamate dehydrogenase as Drug target.