Abstract
Phenylalkylamines (PAAs), a major class of L-type calcium channel (LTCC) blockers, have two aromatic rings connected by a flexible chain with a nitrile substituent. Structural aspects of ligand-channel interactions remain unclear. We have built a KvAP-based model of LTCC and used Monte Carlo energy minimizations to dock devapamil, verapamil, gallopamil, and other PAAs. The PAA-LTCC models have the following common features: (i) the meta-methoxy group in ring A, which is proximal to the nitrile group, accepts an H-bond from a PAA-sensing Tyr_IIIS6; (ii) the meta-methoxy group in ring B accepts an H-bond from a PAA-sensing Tyr_IVS6; (iii) the ammonium group is stabilized at the focus of P-helices; and (iv) the nitrile group binds to a Ca(2+) ion coordinated by the selectivity filter glutamates in repeats III and IV. The latter feature can explain Ca(2+) potentiation of PAA action and the presence of an electronegative atom at a similar position of potent PAA analogs. Tyr substitution of a Thr in IIIS5 is known to enhance action of devapamil and verapamil. Our models predict that the para-methoxy group in ring A of devapamil and verapamil accepts an H-bond from this engineered Tyr. The model explains structure-activity relationships of PAAs, effects of LTCC mutations on PAA potency, data on PAA access to LTCC, and Ca(2+) potentiation of PAA action. Common and class-specific aspects of action of PAAs, dihydropyridines, and benzothiazepines are discussed in view of the repeat interface concept.
Highlights
L-type calcium channels (LTCCs)2 are targets for different drugs
We have chosen four published alignments between Kϩ and Ca2ϩ channels [18, 43,44,45] and highlighted the residues in KvAP that are homologous to the PAA-sensing tyrosines in IIIS5, IIIS6, and IVS6 of LTCC according to these alignments (Fig. 5)
The majority of available data LTCC requires a balance of H-bond acceptors and H-bond donors in the PAA-binding site
Summary
The model in which the amino group of devapamil is located in the inner pore and interacts with the selectivity filter glutamates directly [18] does not explain the Ca2ϩ potentiation of PAA action and the importance of the nitrile group in PAAs. In the ion-conducting state of the channel, these selectivity filter glutamates are involved in the permeation process and bind the permeating ion directly. The geometry of the nitrile group with the lone pair extending from the ligand along the triple-bond direction seems ideal for reaching the Ca2ϩ ion bound to the selectivity filter glutamates. All these considerations suggest that the nitrile group of PAAs interacts directly with the ion at the selectivity filter. The central part of devapamil is located in the inner pore
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