Effects of selective calcium channel blockers on ions' permeation through the human Cav1.2 ion channel: A computational study.

Selective calcium channel antagonists are widely used in the treatment of cardiovascular disorders. They are mainly classified into 1,4-dihydropyridine (1,4-DHPs) and non-DHPs. The non-DHPs class is further classified into phenylalkylamines (PAAs) and benzothiazepines (BZTs) derivatives. These blockers are used for the treatment of hypertension, angina pectoris, and cardiac arrhythmias. Despite their well-established efficiency, the structural basis behind their activity is not very clear. Here we report the use of a near-open confirmation (NOC) model of the Cav1.2 cardiac ion channel to examine the mode of binding of these antagonists within the pore domain as well as the fenestration of the pore-forming domains. Effects of calcium ion permeation in the presence of drug molecules were assessed using steered molecular dynamics (SMD) simulations. These studies reveal that nicardipine, a DHP derivative, shows a strong Cav1.2 blocking activity, requiring more 2500 pN force to pull calcium ion towards the channel's pore in the presence of the compound. Similar blocking activity was observed for verapamil, a PAA derivative, requiring almost 2300 pN of force. The least blocking activity was observed for Diltiazem, a BZT derivative. Our results explain the structural basis and the binding details of 1,4-DHPs, PAAs and BZTs at their distinct Cav1.2 sites and offer detailed insights into their mechanism of action in modulating the Cav1.2 channel. Image 1 • Selective calcium channel blockers (CCBs) include 1,4-dihydropyridine (1,4-DHPs), phenylalkylamines (PAAs) and benzothiazepines (BZTs). • The structural basis behind CCBs' activity is not very clear. • Here we report the use of computational modelling to understand the modes of binding of various selective CCBs and their effects on ion permeation. • Our results explain the binding details of DHPs, PAAs and BZTs at their distinct Ca V 1.2 sites. • Our findings offer detailed insights into the mechanism of action of CCBs in modulating the Ca V 1.2 channel. [ABSTRACT FROM AUTHOR]