Search for human lactate dehydrogenase a inhibitors using structure-based modeling

Abstract

The human lactate dehydrogenase isoform A plays an important role in the anaerobic metabolism of tumour cells and therefore constitutes an attractive target in the oncology field. Full-atom models of lactate dehydrogenase A (in complex with NADH and in the apo form) have been generated to enable structure-based design of novel inhibitors competing with pyruvate and NADH. The structural criteria for the selection of potential inhibitors were established, and virtual screening of a library of low-molecular-weight compounds was performed. A potential inhibitor, STK381370, was identified whose docking pose was stabilized through additional interactions with the loop 96-111 providing for the transition from the open to the closed conformation.