Designed inhibitors with hetero linkers for gastric proton pump H+,K+-ATPase: Steered molecular dynamics and metadynamics studies

Abstract

Acid suppressant SCH28080 and its derivatives reversibly reduce acid secretion activity of the H+,K+-ATPase in a K+ competitive manner. The results on homologation of the SCH28080 by varying the linker chain length suggested the improvement in efficacy. However, the pharmacokinetic studies reveal that the hydrophobic nature of the CH2 linker units may not help it to function as a better acid suppressant. We have exploited the role of linker unit to enhance the efficacy of such reversible acid suppressant drug molecules using hetero linker, i.e., disulfide and peroxy linkers. The logarithm of partition coefficient defined for a drug molecule relates to the partition coefficient, which allows the optimum solubility characteristics to reach the active site. The logarithm of partition coefficient calculated for the designed inhibitors suggests that inhibitors would possibly reach the active site in sufficient concentration like in the case of SCH28080. The steered molecular dynamics studies have revealed that the Inhibitor-1 with disulfide linker unit is more stable at the active site due to greater noncovalent interactions compared to the SCH28080. Centre of mass distance analysis suggests that the Cysteine-813 amino acid residue selectively plays an important role in the inhibition of H+,K+-ATPase for Inhibitor-1. Furthermore, the quantum chemical calculations with M11L/6-31+G(d,p) level of theory have been performed to account the noncovalent interactions responsible for the stabilization of inhibitor molecules in the active site gorge of the gastric proton pump at different time scale. The hydrogen bonding and hydrophobic interaction studies corroborate the center of mass distance analysis as well. Well-tempered metadynamics free energy surface and center of mass separation analysis for the Inhibitor-1 is in good agreement with the steered molecular dynamics results. The torsional angle of the linker units seems to be crucial for better efficacy of drug molecules. The torsional angle of linker units of SCH28080 (COCH2C) and of Inhibitor 1 (CSSC) prefers to lie within ∼60°–90° for a longer time during the simulations, whereas, the peroxy linker (COOC) of Inhibitor 2 prefers to adopt ∼120–160°. Therefore, it appears that the smaller torsion angle of linker units can achieve better interactions with the active site residues of H+,K+-ATPase to inhibit the acid secretion activity. The reversible drug molecules with disulfide linker unit would be a promising candidate as proton pump antagonist to H+,K+-ATPase.