Exploring the mechanism of H,K-ATPase interaction with Tegoprazan; from rapid kinetics of binding to molecular dynamics studies.

CERF NT; FERNÁNDEZ LUGO GA; ROSSI RC; FILOMATORI C; ZERBETTO DE PALMA G; FARAJ SE; MONTES MR

Córdoba, Provincia de Córdoba, Argentina

Congreso; LI Reunión Anual de la Sociedad Argentina de Biofísica; 2023

Sociedad Argentina de Biofísica

The gastric H,K-ATPase is responsible for stomach acidification by pumping H+ ions in exchange for extracellular K+ ions. Because of its location in the membrane of parietal cells, the H,K-ATPase is the primary target for treating acid-related disorders. An innovative strategy was the development of "potassium competitive acid blockers" (PCABs), which binds in an extracellular hydrophobic pocket of the protein making it difficult for K+ to enter its binding site, resulting in a rapid increase of intra-gastric pH (1). In contrast to omeprazole and its derivatives, PCABs are proposed to reversibly bind to the H,K-ATPase, without requiring acid activation. However, here we show that Tegoprazan, a PCAB inhibitor, exhibits increased affinity for the H,K-ATPase as H+ concentration rises. To understand this effect, we conducted in vitro and in silico experiments to analyze the interaction between the "proton pump", H+ ions and Tegoprazan. Our results uncover potential factors contributing to the enhanced efficacy of tegoprazan at low pH.Keywords: H,K-ATPase, conformational changes, enzyme inhibition, bindingReferences:(1)-Tanaka, S., Morita, M., Yamagishi, T., Madapally, H. V., Hayashida, K., Khandelia, H.,Gerle, C., Shigematsu, H., Oshima, A., & Abe, K. (2022).. Journal of medicinal chemistry, 65(11), 7843-7853.