Artificial intelligence-driven identification of morin analogues acting as Ca V 1.2 channel blockers: Synthesis and biological evaluation

• Published in: Bioorganic chemistry 2023-02, Vol.131, p.106326
• Main Authors: Carullo, Gabriele, Falbo, Federica, Ahmed, Amer, Trezza, Alfonso, Gianibbi, Beatrice, Nicolotti, Orazio, Campiani, Giuseppe, Aiello, Francesca, Saponara, Simona, Fusi, Fabio
• Format: Article
• Language: English
• Subjects: Animals; Artificial Intelligence; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - metabolism; Flavonoids - pharmacology; Rats; Vasodilation; Vasodilator Agents - chemistry; Vasodilator Agents - pharmacology
• ISSN: 1090-2120

Morin is a vasorelaxant flavonoid, whose activity is ascribable to Ca 1.2 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 Ca 1.2 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 Ca mobilization from intracellular store sites. Furthermore, 5a≈5c > 5b inhibited Ba current through Ca 1.2 channels. However, compound 5a caused also a concentration-dependent inhibition of K 1.1 channel currents.