Open AccessSeeking the exclusive binding region of phenylalkylamine derivatives on human T‐type calcium channels via homology modeling and molecular dynamics simulation approach
Author(s) -
Lu You,
Li Ming,
Lee Gi Young,
Zhao Na,
Chen Zhong,
Edwards Andrea,
Zhang Kun
Publication year - 2021
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.783
Subject(s) - molecular dynamics , docking (animal) , calcium channel , mibefradil , homology modeling , calcium , l type calcium channel , cav1.2 , chemistry , voltage dependent calcium channel , biophysics , computational biology , bioinformatics , biology , biochemistry , computational chemistry , medicine , enzyme , nursing , organic chemistry
Pharmaceutical features of phenylalkylamine derivatives (PAAs) binding to calcium channels have been studied extensively in the past decades. Only a few PAAs have the binding specificity on calcium channels, for example, NNC 55‐0396. Here, we created the homology models of human Ca v 3.2, Ca v 3.3 and use them as a receptor on the rigid docking tests. The nonspecific calcium channel blocker mibefradil showed inconsistent docking preference across four domains; however, NNC 55‐0396 had a unique binding pattern on domain II specifically. The subsequent molecular dynamics (MD) simulations identified that Ca v 3.1, Ca v 3.2, and Ca v 3.3 share domain II when Ca 2+ appearing in the neighbor region of selective filters (SFs). Moreover, free‐energy perturbation analysis suggests single mutation of lysine at P‐loop domain III, or threonine at the P‐loop domain II largely reduced the total amount of hydration‐free energy in the system. All these findings suggest that P‐loop and segment six domain II in the T‐type calcium channels (TCCs) are crucial for attracting the PAAs with specificity as the antagonist.