Characterizing the 1,4-dihydropyridines binding interactions in the L-type Ca2+ channel: model construction and docking calculations.
L-type Ca2+ channels (LCC) are membrane heteromultimeric proteins that allow the selective entrance of Ca2+ ions into excitable cells upon membrane depolarization. Despite the large amount of compounds (1,4-dihydropyridines, phenylalkylamines, and benzothiazepines) that impede the passage of Ca2+ ions through the channel, it is still not clear how these molecules bind to LCC at an atomic level. In this study, a 3D model of the central pore of LCC was constructed using the X-ray structure of the KcsA K+ channel as template. The resulting LCC model was then used to dock nine different DHPs to shed light on their binding mode. The accordance between the developed model and several experimental data gives us the confidence to propose our model as a valuable platform for future studies aimed at the identification of new potent and LCC-selective ligands.
Cosconati
Sandro
S
Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy. scoscona@unina.it
Marinelli
Luciana
L
Lavecchia
Antonio
A
Novellino
Ettore
E
D000595:Amino Acid Sequence; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D008024:Ligands