Binding modes study on enantiomers of BYK 311319 as potassium competitive acid blockers

Xing-Xing Xian-Yu1, Cong Wu1,

Abstract

Potassium-competitive acid blocker (9S)-BYK 311319 (pIC50=6.8) showed significantly higher inhibition activity than (9R)-enantiomer (pIC50=5.4). Here the binding modes of BYK 311319 enantiomers with H+,K+-ATPase were studied by Homology modeling, induced-fit docking (IFD), molecular dynamics and MM/GBSA calculation methods. The docking Gscores, IFD scores and ΔGbind (binding free energies) of (9S)-BYK 311319 (-9.64, -1724.74 and - 47.71 kcal/mol) are more favorable than those of (9R)-enantiomer (-6.98, -1723.88 and -43.14 kcal/mol), which is consistent with the experimental inhibition activities. (9S)-BYK 311319 has hydrogen bond interaction with the key residue Cys813 and interacts with residues Gln127, Thr135, Asp136, Asp137 and Asn138 in the TM1-2 loop of H+,K+-ATPase through charged interactions