Molecular docking studies of Amidoxime-containing heterocyclic compounds from Zinc database against homology modelled PfADSL

Abstract

Abstract Malaria remains one of the most infectious life-threatening diseases in the world. The lingering effect of drug resistance by malarial parasites, especially Plasmodium falciparum, has made it essential for the continuous search for novel antimalarial drugs that can act on new protein targets and through new modes of action. Amidoxime functional groups have, in recent years, shown to be good incorporations in heterocyclic backbones due to their vast biological activities. Hence, the antimalarial activities of some amidoxime-containing heterocyclic compounds have been predicted using molecular docking studies to determine the binding affinities and the inhibition constants of the compounds. The amidoxime-containing compounds were downloaded from the ZINC database and docked, using Auto Dock vina, against the active sites of homology modelled Plasmodium falciparumadenylosuccinate lyase (PfADSL) as obtained from the SWISS-MoDeL. The grid box was constructed using 80, 80, and 80, pointing in x, y, and z directions, respectively, with a grid point spacing of 0.375 A. The post-docking analysis, which entails determining the hydrogen bond formed and the bond length between the compounds and the protein target, was carried out using AutoDockTools, LigPlot and PyMOLmolecular viewer. The docking studies showed that the compounds possess binding affinities ranging from -8.6 to- 5.7 kcal/mol, with ZINC2268942 having the lowest binding affinity. The presence of the amidoxime-functional group on the best hit contributed significantly to the hydrogen bonds formed between the compound and the binding sites of PfADSL,which were observed atThr 124D, Ser 125D, Thr 172C, His 173C, Gln 250D, and Ser 299A. The results obtained from the molecular docking studies will be helpful in the development of a potential antimalarial drug that can target PfADSL after careful experimental validation of the target, then in vitro and in vivo screening.