Reversible acid suppressants represent a new therapeutic option for the treatment of acid-related diseases. The forces responsible for the interaction of reversible inhibitors with gastric pump H⁺,K⁺-ATPase is less explored. Quantum chemical calculations reveals that the drug molecule is mainly stabilized by non-covalent interactions, such as Π-Π, cation-Π, and NH-Π, with the active amino acid residues of the H⁺,K⁺-ATPase enzyme. The M062X/6-311++G(d,p) level of theory calculated interaction energy of SCH28080 is 149.52 kJ/mol and 148.26 kJ/mol for K⁺ ion with the inhibitor binding site amino acid residues. The results suggest that SCH28080 can block the acid secretion activity of gastric proton pump in the parietal cells. The designed Inhibitor-3 structurally similar to the SCH28080 enjoys better non-covalent interactions. We have also performed well-tempered metadynamics (WTMtD) simulations of the protein-drug complexes which corroborate the findings from DFT calculations. Our computational study demonstrated that noncovalent interactions are responsible for the inhibitor binding at the inhibitor binding site of H⁺,K⁺-ATPase.