Development of new antimalarial drugs continues to be of great importance due to the resistance of the malaria parasite to currently used drugs. Glycolytic enzymes have emerged as potential targets for the development...Development of new antimalarial drugs continues to be of great importance due to the resistance of the malaria parasite to currently used drugs. Glycolytic enzymes have emerged as potential targets for the development of new drugs due to the reliance of the parasite on glycolysis for energy. In this study, molecular docking was used to study the binding of some quinoline-based drugs to the glycolytic enzyme lactate dehydrogenase. The docking studies identified two potential binding sites for each ligand, one of them being the cofactor-binding site. For all ligands studied, there was the comparable binding to the cofactor-binding site as well as the secondary binding site when the cofactor was absent. All ligands showed significantly lower binding affinity than NADH for the cofactor binding site. The alternative site was the site of preference when docking was done in the presence of the cofactor. While binding to the cofactor site may support other studies suggesting potential for competitive inhibition, the fact that the binding affinities of all the ligands are significantly lower than that for NADH in this site suggests that these ligands will be ineffective competitive inhibitors. The identification of an alternative binding site with comparable affinity that is not affected by the presence of the cofactor may suggest the possibility of non-competitive inhibition that requires further exploration.展开更多
文摘Development of new antimalarial drugs continues to be of great importance due to the resistance of the malaria parasite to currently used drugs. Glycolytic enzymes have emerged as potential targets for the development of new drugs due to the reliance of the parasite on glycolysis for energy. In this study, molecular docking was used to study the binding of some quinoline-based drugs to the glycolytic enzyme lactate dehydrogenase. The docking studies identified two potential binding sites for each ligand, one of them being the cofactor-binding site. For all ligands studied, there was the comparable binding to the cofactor-binding site as well as the secondary binding site when the cofactor was absent. All ligands showed significantly lower binding affinity than NADH for the cofactor binding site. The alternative site was the site of preference when docking was done in the presence of the cofactor. While binding to the cofactor site may support other studies suggesting potential for competitive inhibition, the fact that the binding affinities of all the ligands are significantly lower than that for NADH in this site suggests that these ligands will be ineffective competitive inhibitors. The identification of an alternative binding site with comparable affinity that is not affected by the presence of the cofactor may suggest the possibility of non-competitive inhibition that requires further exploration.
