Molecular Modeling of Interactions of Dihydropyridines and Phenylalkylamines with the Inner Pore of the L-Type Ca²⁺Channel

Abstract

Domains IIIS5, IIIS6, and IVS6 transmembrane segments of L-type Ca 2ϩ channels participate in dihydropyridine (DHP) and phenylalkylamine (PAA) binding. The inner pore structure of the Ca v 1.2 channel was reconstructed from coordinates of the transmembrane ␣-helices of the KcsA channel. S6s were aligned with M2 by comparative analysis of the pore-facing M2 side chains and those required for drug binding. Two neighboring tilted S6 helices of domains III and IV below the selectivity filter formed an interdomain crevice. Docking of DHPs inside this crevice located the DHP ring between Phe-1159 of IIIS6 and Ala-1467 of IVS6, parallel to the pore axis, whereas the 4-aryl ring participated in aromatic and polar interactions with the side chains of Tyr-1152 and Tyr-1463. Nonpolar interactions of the port side ester group with hydrophobic side chains of Ile-1156, Ile-1163, and Ile-1471 on the bottom of the binding cavity, formed by the crossover of IIIS6 and IVS6, could stabilize the channel's closed/inactivated state. Similar arrangements were found for DHP agonist drugs, except for the absence of hydrophobic interactions with the helical crossing. In this arrangement, DHPs do not physically block the pore. Locating the central amine group of desmethoxyverapamil near the selectivity filter domain III glutamic acid allows one aromatic ring through its CH 2 CH 2 linker to interact with the side chain of Tyr-1463 inside the DHP binding site, whereas the opposite aromatic ring is in contact with the side chain of Ile-1470 of IVS6, blocking the pore.

Competitive and Cooperative Effects of Bay K8644 on the L-Type Calcium Channel Current Inhibition by Calcium Channel Antagonists

“…The interaction between DHP and BTZ/PAA takes place within the small space to which their binding sites are confined at the ␣ 1 subunit of the channel (Lipkind and Fozzard, 2003;Yamaguchi et al, 2003). Therefore, the interaction between the drugs and Bay K8644 probably has a strong steric component, as suggested for verapamil by Kraus et al (1998).…”

Structural Basis for Pharmacology of Voltage-Gated Sodium and Calcium Channels

“…Molecular models of dihydropyridine binding have been developed based on the structures of the KcsA and KvAP potassium channels (Lipkind and Fozzard, 2003). These models place the bound drug at the interface between domains III and IV in a position to interact with amino acid residues in the IIIS5, IIIS6, and IVS6 segments, as observed in structurefunction studies .…”

“…Molecular modeling and ligand-docking methods have been used to predict the binding pose of the phenylalkylamines in their receptor site (Lipkind and Fozzard, 2003;Cheng et al, 2009). In the initial study, based on the structure of the KcsA potassium channel, the bound phenylakylamine was fit in a half-folded, L-shaped conformation, with the positively charged ammonium group projecting toward the negatively charged ion selectivity filter, aromatic ring A in the central cavity, and aromatic ring B projecting toward the interface between domains III and IV (Lipkind and Fozzard, 2003).…”

“…In the initial study, based on the structure of the KcsA potassium channel, the bound phenylakylamine was fit in a half-folded, L-shaped conformation, with the positively charged ammonium group projecting toward the negatively charged ion selectivity filter, aromatic ring A in the central cavity, and aromatic ring B projecting toward the interface between domains III and IV (Lipkind and Fozzard, 2003). In the second model, based on the KvAP structure, the elongated phenylalkylamine molecule is predicted to lie in a more extended conformation, with the conserved nitrile group projecting toward the ion selectivity filter with Ca 21 bound in it, the positively charged ammonium group placed at the axis of the pore in the focus of the helical dipole of the four P-helices, and the aromatic rings and methoxy groups making hydrophobic and hydrogen-binding interactions with amino acid side chains and the backbone of the S6 segments (Cheng et al, 2009).…”

Calcicludine Binding to the Outer Pore of L-type Calcium Channels Is Allosterically Coupled to Dihydropyridine Binding

“…The domain-interface theory predicts that allosteric ligands bind at structural interfaces, possibly because the receptor protein is most flexible in such regions (7,(27)(28)(29)(30)(31). The domain interface theory can be used to explain how the calcicludine and DHP binding sites are allosterically coupled, as well.…”