title: Molecular simulations study of novel 1,4-dihydropyridines derivatives with a high selectivity for Cav3.1 calcium channel.
abstract: 1,4-Dihydropyridines (DHPs) have been developed to treat hypertension, angina, and nerve system disease. They are thought to mainly target the L-type calcium channels, but low selectivity prompts them to block Cav1.2 and Cav3.1 channels simultaneously. Recently, some novel DHPs with different hydrophobic groups have been synthesized and among them M12 has a higher selectivity for Cav3.1. However, the structural information about Cav3.1-DHPs complexes is not available in the experiment. Thus, we combined homology modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations to quantitatively elucidate the inhibition mechanism of DHPs. The calculated results indicate that our model is in excellent agreement with experimental results. On the basis of conformational analysis, we identify the main interactions between DHPs and calcium channels and further elaborate on the different selectivity of ligands from the micro perspective. In conjunction with energy distribution, we propose that the binding sites of Cav3.1-DHPs is characterized by several interspersed hydrophobic amino acid residues on the IIIS6 and IVS6 segments. We also speculate the favorable function groups on prospective DHPs. Besides, our model provides important information for further mutagenesis experiments.
authors.affiliation: State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, 130023, People's Republic of China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Chemistry Teaching Center, College of Chemistry and Biology, Beihua University, Jilin, 132013, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, 130023, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, 130023, People's Republic of China.
authors.forename: Xu-Ri
authors.initials: XR
authors.lastname: Huang
mesh_terms: D020747:Calcium Channels, T-Type / Q000737:chemistry* / Q000378:metabolism*; D004095:Dihydropyridines / Q000737:chemistry* / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D056004:Molecular Dynamics Simulation
chemical_list: C121855:CACNA1G protein, human; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; C038806:1,4-dihydropyridine
keywords: Cav3.1-1,4-dihydropyridines-binding sites; drug molecular design; molecular dynamics simulation; selectivity for Cav3.1 channel