Abstract
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides that contribute to the regulation of intestinal motility and secretion, exocrine and endocrine secretions, and homeostasis of the immune system. Their biological effects are mediated by three receptors named VPAC1, VPAC2 and PAC1 that belong to class B GPCRs. VIP and PACAP receptors have been identified as potential therapeutic targets for the treatment of chronic inflammation, neurodegenerative diseases and cancer. However, pharmacological use of endogenous ligands for these receptors is limited by their lack of specificity (PACAP binds with high affinity to VPAC1, VPAC2 and PAC1 receptors while VIP recognizes both VPAC1 and VPAC2 receptors), their poor oral bioavailability (VIP and PACAP are 27- to 38-amino acid peptides) and their short half-life. Therefore, the development of non-peptidic small molecules or specific stabilized peptidic ligands is of high interest. Structural similarities between VIP and PACAP receptors are major causes of difficulties in the design of efficient and selective compounds that could be used as therapeutics. In this study we performed structure-based virtual screening against the subset of the ZINC15 drug library. This drug repositioning screen provided new applications for a known drug: ticagrelor, a P2Y12 purinergic receptor antagonist. Ticagrelor inhibits both VPAC1 and VPAC2 receptors which was confirmed in VIP-binding and calcium mobilization assays. A following analysis of detailed ticagrelor binding modes to all three VIP and PACAP receptors with molecular dynamics revealed its allosteric mechanism of action. Using a validated homology model of inactive VPAC1 and a recently released cryo-EM structure of active VPAC1 we described how ticagrelor could block conformational changes in the region of ‘tyrosine toggle switch’ required for the receptor activation. We also discuss possible modifications of ticagrelor comparing other P2Y12 antagonist – cangrelor, closely related to ticagrelor but not active for VPAC1/VPAC2. This comparison with inactive cangrelor could lead to further improvement of the ticagrelor activity and selectivity for VIP and PACAP receptor sub-types.
Highlights
Finding new therapeutic purposes for registered drugs is one of the major directions in modern pharmacology
Using carboxyfluorescein-labelled Vasoactive intestinal peptide (VIP) as tracer, we evaluated by fluorescence-activated cell sorting (FACS) analysis the ability of compounds to compete with VIP binding to VPAC1 and VPAC2 receptors
In the presence of difficulties in drug discovery for VIP and pituitary adenylate cyclase-activating polypeptide (PACAP) signalling pathways we presented an alternative approach based on the drug repositioning concept
Summary
Finding new therapeutic purposes for registered drugs is one of the major directions in modern pharmacology. Drug formulation or route of administration still may require adjustments to account for newly discovered pharmacodynamics effects, most of preclinical and clinical tests can be omitted. Many of repurposed drugs were discovered by chance, e.g., well-known thalidomide [2], by making use of observed side-effects. This way, drugs that failed in clinical trials due to insufficient efficacy [3] could be given a second chance [4, 5]. Systematic approaches involving screening of known active medicines have been used [6], e.g., in repositioning of antifungal itraconazole as a new anticancer drug [7]. E.g., SARS-CoV-2, time pressure is another reason for turning to drug repurposing in pharmacotherapy [11]
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