Abstract
Marine natural products represent a diverse collection of structurally distinct metabolites, many of which have untapped therapeutic potential. This study screened 161 marine-derived coumarin and xanthene compounds for their binding affinity to the histamine H₂ receptor and the gastric H⁺/K⁺-ATPase, the primary regulators of gastric acid secretion. Docking simulations were performed using curated structures of both targets, followed by an evaluation of the compounds for drug-likeness and predicted absorption, distribution, metabolism, and excretion (ADME) properties. Thirty-four compounds demonstrated a stronger predicted affinity for the H₂ receptor than famotidine; however, only three compounds (1, 5, and 150) met all drug-likeness criteria, achieving quantitative estimates of drug-likeness (QED) values exceeding 0.67. Screening against the proton pump yielded 98 hits with higher affinity than soraprazan, with compound 150 being the only candidate to fulfill all medicinal chemistry filters. Interaction analysis indicated that compound 150 binds to the proton pump in a manner that largely overlaps with soraprazan. Density functional theory (DFT) calculations were utilized to characterize the electronic properties of the most promising compounds. ADME predictions suggested favorable permeability and a low risk for human ether-à-go-go-related gene (hERG) inhibition, although high plasma protein binding and the potential for cytochrome P450 (CYP) inhibition may require further optimization. These findings underscore the potential of pyranocoumarin compound 150, along with xanthene derivatives 1 and 5, as promising candidates for the development of new acid-suppressive agents.