Molecular docking studies on N-hydroxyindole derivatives as potent inhibitors of human lactate dehydrogenase isoform 5 against cancer cell proliferation

Abstract

Most metastatic cancer cells show a metabolic switch from normal oxidative phosphorylation to an increased rate of glycolysis named as the “Warburg effect.” Thus, even under hypoxic environments, Warburg effect provides a sufficient supply of energy from glucose. Isoform 5 of human lactate dehydrogenase (hLDH5) catalyzes the final step in the glycolysis (pyruvate to lactate) and constitutes a new anticancer target. In silico methods were employed to study the inhibitory property of the N-Hydroxyindole-based compounds against hLDH5. The compound ligands are subjected to Standard Precision (SP) docking and Extra Precision (XP) docking in GLIDE against the target protein hLDH5 [PDB ID: 1I10] each at the active site and at the cofactor binding site. Based on the docking score, glide energy, and hydrogen bonding interactions, six best compounds are selected and further subjected to Induced Fit Docking. Absorption, distribution, metabolism, and excretion (ADME) properties of the ligands are analyzed using QikProp. All computational methods are performed using Schrodinger suite 2009 USA. Compound 3m (6-[4-(2-carboxyethyl)phenyl]-1-hydroxy-1H-indole-2-carboxylic acid) showed the best conformational fit compared to the reference inhibitors.