Molecular Dynamics Simulations Study The Inhibitory Mechanism Of 1,4-dihydropyridines Derivatives On Calcium Channel

Ion channels facilitate the diffusion of ions across the cellular membrane and are major components of the nervous system. They play crucial roles in variety of physiological processes such as smooth muscle contractions and release of neurotransmitters. They are important molecular targets for the treatment of many human diseases. Along with the development of computer technology and computing method, molecular dynamics simulation has been widely used in the research of the macromolecular structural feature and functional mechanism in biological system. Molecular dynamics simulation can reveal the essential rules of the activity of biological protein at the molecular and atomic level, and provides theoretical support for the corresponding experimental research and drug clinical trials.In recent decades, 1,4-Dihydropyridines(DHPs) have been developed to treat hypertension, angina and nerve system diseases. As a kind of most widely used inhibitors, they block the calcium channel efficiently and mainly target the L-type calcium channels. But their low selectivity prompts them to block Cav1.2 and Cav3.1 calcium channels simultaneously. It may lead to the drug side effects and potential physiological hazard. Recently, some novel DHPs derivatives with different hydrophobic groups have been synthesized and evaluated by researchers. And among them, M12 molecule has a higher selectivity for Cav3.1 calcium channel. However, the structural information about Cav3.1-DHPs complexes is not available in the experiment.In this article, we combined homology modeling, molecular docking, molecular dynamics simulations and binding free energy calculations to study the inhibition mechanism of novel 1,4-dihydropyridines derivatives on L-type calcium channel and T-type calcium channel. MD simulation results show that our Cav3.1 model and complexes structures are extraordinarily stable. The calculated binding free energies indicate that our model is in excellent agreement with experimental results. On the basis of conformational analysis of first series and second series, we identify the main interactions between DHPs derivatives and calcium channels. And we further study the different binding free energies of ligands from the micro perspective. Different hydrophobic effects of two calcium channels result in that M12 molecule exhibits a strong selectivity for Cav3.1 calcium channel. In conjunction with MD simulation results, energy distribution reveals that the binding sites of Cav3.1-DHPs is characterized by several interspersed hydrophobic amino acids on the IIIS6 and IVS6 segments. Besides, our results provide important information for further mutagenesis experiments and designing the new pharmacophore of calcium channel blockers.