evaluation of binding propensities of plant-derived compounds to l-type and t-type voltage-dependent calcium channels through molecular docking: a comparison with amlodipine

This study aimed to investigate in silico the binding propensities and potential binding modes of plant-derived compounds (carvacrol, thymol, eugenol, oleuropein) to cav1.2 and cav3.2 subtypes, as compared to the antihypertensive calcium channel blocker amlodipine. receptor structures were obtained and prepared from rcsb pdb (cav1.2: 8we8, cav3.2: 9ayg). potential binding pockets were scanned using cb-dock2; pockets yielding the best scores for amlodipine were selected, and grids were defined accordingly (cav1.2: c4, cav3.2: c5; with an additional +5 å safety margin for dimensions). ligands were retrieved from pubchem in 3d-sdf format, protonated at ph 7.4 using open babel, assigned gasteiger charges, and converted to pdbqt. blind docking simulations were performed with autodock vina v1.2.7 using uniform parameters (exhaustiveness = 8, num_modes = 10, seed = 12345). the best modes were converted into 2d interaction maps using biovia discovery studio visualizer. according to vina, the binding free energies (δg, kcal·mol⁻¹) for cav1.2/c4 were: oleuropein −8.010, amlodipine −6.339, eugenol −5.599, carvacrol −5.592, thymol −5.177; and for cav3.2/c5: oleuropein −6.817, amlodipine −6.078, carvacrol −5.792, thymol −5.476, eugenol −4.939. oleuropein consistently yielded better/similar scores than amlodipine in both targets, demonstrating a notable superiority, particularly in cav1.2 (δδg s ≈ −1.2). 2d maps revealed that oleuropein is stabilized by multiple h-bonds (ser/asp/asn/gln) and π-interactions, whereas binding of phenolic monoterpenes (carvacrol/thymol/eugenol) primarily involves hydrophobic/π-alkyl characteristics. the larger volume of the c4 pocket (~2.9×10³ å³) explains the more advantageous binding of bulky ligands (oleuropein/amlodipine) in c4, while the more compact c5 exhibits relative superiority for smaller phenolics. oleuropein emerged as a prominent compound in calcium channel subtypes—especially in cav1.2—exhibiting binding energies surpassing the reference amlodipine and a robust network of h-bonds and π-stacking. these findings provide pharmacophore insights (multiple h-bond donor/acceptor motifs + aromatic surface) for rational derivative design. validation of selected poses through molecular dynamics simulations and electrophysiological tests will contribute to elucidating subtype selectivity.