Preliminary Identification of Lactate Dehydrogenase Inhibitors towards Anticancer Drug Development

Abstract

In tumor cells undergoing rapid cellular division, significantly increased quantities of lactic acid are produced in an anaerobic respiration via the Cori cycle. While this produces a lower of the pH in the local environment, the hepatic conversion of the generated lactate into glucose places a huge energy demand on the body which makes the patient weaker and results in cancer cachexia. Thus, instead of producing acetyl CoA, the dividing tumorous cells synthesize lactic acid catalyzed by the enzyme lactate dehydrogenase (LDH). LDH’s involvement in tumor initiation and metabolism primarily involves a state of fermentative glycolysis catalyzed by the A form of the enzyme which allows tumorous cells convert the majority of their glucose stores into lactate even under anaerobic conditions which invariably shifts the utilization of glucose metabolites from simple energy production to an active promotion of accelerated cell growth and replication. This makes LDH a vital target for drug development. And in the present work a combination of virtual screening, database scouting and biophysical analysis of binding site properties have been employed in analysis the interaction of about 30,000 compounds with LDH. Using a synthetic NADH inhibitor, as a reference, only four compounds were found to demonstrate stronger binding features than the inhibitor. This preliminary in silicon screening represents the foundational effort in a cancer drug discovery project aimed at generating specific inhibitors of LDH for use in cancer therapeutics.