# Virtual screening of marine coumarins and xanthenes identifies novel acid-suppressive leads targeting histamine H2 receptor and gastric proton pump

## TL;DR

This study identifies new marine compounds that could suppress stomach acid by targeting key receptors and proton pumps.

## Contribution

The study introduces novel marine-derived compounds with strong binding affinity to acid suppression targets.

## Key findings

- Compound 150 showed higher affinity to the proton pump than soraprazan and met all drug-likeness criteria.
- Three compounds (1, 5, and 150) exceeded drug-likeness thresholds for the H2 receptor.
- ADME predictions suggest favorable properties but highlight potential for CYP inhibition and high plasma protein binding.

## 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.