Asthma remains a disease that inflicts a large economic cost on health care systems with only marginal improvement in health outcomes. Up to 50% of asthma patients are unable to achieve adequate control of symptoms and there remains a need for additional therapeutic classes of drugs that mediate bronchodilation through novel molecular mechanisms. Interestingly, various isoforms of bitter taste receptors (TAS2Rs) were found to be expressed in human airway smooth muscle, where TAS2R14 has the greatest expression level. The discovery that agonists of TAS2R14 promote smooth muscle relaxation in various disease models of asthma has established the therapeutic potential of these agents as a novel class of bronchodilators. Extensive molecular modeling was performed to develop models of TAS2R14 bound to reference agonists. An ensemble of homology models was constructed and subjected to flexible-receptor docking using CHARMM. Flexible-receptor docking was utilized to select the best low energy models by docking large rigid reference ligands with few rotatable bonds (such as aristolochic acid, absinthin and quassin). This strategy was utilized as receptor-ligand binding modes of such large and rigid ligands may be determined with a greater level of confidence compared to extremely flexible reference ligands. The best models of TAS2R14 bound to these reference ligands exhibited convincing superposition of various ligand pharmacophore features. Once the best models had been selected, these were used to model other TAS2R14 ligands reported in the literature and develop a virtual screening strategy.

Flexible-receptor docking for ligands of G protein coupled receptor TAS2R14: Target for bronchodilation

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.