Artificial intelligence-driven identification of morin analogues acting as CaV1.2 channel blockers: Synthesis and biological evaluation.

Gabriele Carullo, Federica Falbo, Amer Ahmed, Alfonso Trezza, Beatrice Gianibbi, Orazio Nicolotti, Giuseppe Campiani, Francesca Aiello, Simona Saponara, Fabio Fusi

Bioorganic chemistry 2023 Feb

filter terms:

Morin is a vasorelaxant flavonoid, whose activity is ascribable to CaV1.2 channel blockade that, however, is weak as compared to that of clinically used therapeutic agents. A conventional strategy to circumvent this drawback is to synthesize new derivatives differently decorated and, in this context, morin-derivatives able to interact with CaV1.2 channels were found by employing the potential of PLATO in target fishing and reverse screening. Three different derivatives (5a-c) were selected as promising tools, synthesized, and investigated in in vitro functional studies using rat aorta rings and rat tail artery myocytes. 5a-c were found more effective vasorelaxant agents than the naturally occurring parent compound and antagonized both electro- and pharmaco-mechanical coupling in an endothelium-independent manner. 5a, the series' most potent, reduced also Ca2+ mobilization from intracellular store sites. Furthermore, 5a≈5c > 5b inhibited Ba2+ current through CaV1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of KCa1.1 channel currents. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Gabriele Carullo, Federica Falbo, Amer Ahmed, Alfonso Trezza, Beatrice Gianibbi, Orazio Nicolotti, Giuseppe Campiani, Francesca Aiello, Simona Saponara, Fabio Fusi. Artificial intelligence-driven identification of morin analogues acting as CaV1.2 channel blockers: Synthesis and biological evaluation. Bioorganic chemistry. 2023 Feb;131:106326