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Drug Repositioning For Allosteric Modulation of VIP and PACAP Receptors.
1Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Faculty of Medicine, Université libre de Bruxelles, Brussels, Belgium.
Frontiers in Endocrinology
|December 6, 2021
Summary
Ticagrelor, a known drug, was found to inhibit VIP and PACAP receptors (VPAC1 and VPAC2). This discovery offers potential new therapeutic strategies for diseases involving these receptors.
Area of Science:
- Pharmacology
- Molecular Biology
- Drug Discovery
Background:
- Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) regulate vital physiological processes.
- Their receptors (VPAC1, VPAC2, PAC1) are therapeutic targets for inflammation, neurodegeneration, and cancer.
- Limitations of current peptide ligands include poor specificity, bioavailability, and short half-life.
Purpose of the Study:
- To identify non-peptidic small molecules targeting VIP and PACAP receptors.
- To explore drug repositioning for novel therapeutic applications.
- To investigate the mechanism of action for potential drug candidates.
Main Methods:
- Structure-based virtual screening of the ZINC15 drug library.
- In vitro assays including VIP-binding and calcium mobilization.
- Molecular dynamics simulations to analyze binding modes and allosteric mechanisms.
- Comparative analysis with related compounds like cangrelor.
Main Results:
- Ticagrelor, a P2Y12 antagonist, was identified as an inhibitor of VPAC1 and VPAC2 receptors.
- Confirmed ticagrelor's inhibitory effects through binding and functional assays.
- Elucidated ticagrelor's allosteric mechanism of action on VPAC1, involving the 'tyrosine toggle switch' region.
- Identified structural insights for improving ticagrelor's selectivity and activity.
Conclusions:
- Ticagrelor represents a promising non-peptidic small molecule for targeting VPAC1 and VPAC2 receptors.
- Drug repositioning of ticagrelor offers a novel therapeutic avenue for diseases linked to VIP/PACAP signaling.
- Further optimization based on structural analysis could enhance ticagrelor's efficacy and selectivity.
Keywords:
G protein-coupled receptorsallosteric modulatormolecular dynamicsneuropeptidespituitary adenylate cyclase activating polypeptideticagrelorvasoactive intestinal polypeptidevirtual screeningMore Related Videos
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