ИСТИНА

Human lactate dehydrogenase A (LDH-A) plays a significant role in the glucose metabolism of cancer cells and constitutes an attractive target for chemotherapy. The active site of LDH-A includes substrate-binding and coenzyme-binding sites. Also, an additional binding site is formed upon the transition of the mobile loop 96-111 into the open conformation, which may be important for the design of new inhibitors. In this work the structural criteria for the selection of promising inhibitors were established and virtual screening of a large library of chemical compounds was performed. By analysis of binding of substrates and known inhibitors, we indentified the residues forming the most imortant interactions: Arg168, Arg105 and Thr247. Models of the closed and open forms of human LDH-A have been constructed based on the crystal structures 1i10 and 4l4s using the Amber package. Molecular docking of 2379 ZINC compounds with sulfo group (isosteric analogue of the carboxyl substrateʼs group) into the active site of protein models was done using Lead Finder. Next, we have applied the established structural criteria (hydrogen bonds with Arg168, Arg105 and Thr247, as well as additional interactions with His192, Asn137, Gln99 и Ile241 residues), which allowed us to select 4% of compounds as putative inhibitors of the closed LDH-A form and 5% of compounds as inhibitors of the open form. This work was supported by the The Foundation for Assistance to Small Innovative Enterprises in Science and Technology (FASIE) “UMNIK”(contract № 12449GU/2017).