title: Comparison of lowest energy conformations of dimethylcurine and methoxyverapamil: evidence of ternary association of calcium channel, Ca2+, and calcium entry blockers.
abstract: Verapamil and dimethylcurine are Ca2+ entry blockers of essentially different chemical structures which presumably bind to the same arylalkylamine receptor of the L-type Ca channel. A systematic conformational analysis of methoxyverapamil (D-600) and dimethylcurine has been carried out using a molecular mechanics method. The lowest minimum-energy conformations of D-600 are predisposed to chelate Ca2+ by four oxygen atoms of the stacked methoxyphenyl moieties. Comparison of the lowest energy conformations of D-600-Ca2+ and dimethylcurine revealed a similar spatial disposition of cationic groups and methoxyphenyl moieties in the two compounds. A three-dimensional model of arylalkylamine receptor was suggested which incorporates two nucleophilic areas of the Ca channel. Dimethylcurine binds to these areas by its quaternary amine functions, whereas D-600 does so by amine function and via coordinated Ca2+. The results support the hypotheses on ternary complex formation between the ligands of Ca channel, their receptors, and Ca2+.
authors.affiliation: Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
authors.forename: B S
authors.initials: BS
authors.lastname: Zhorov
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D003198:Computer Simulation; D004365:Drugs, Chinese Herbal / Q000737:chemistry* / Q000378:metabolism*; D005711:Gallopamil / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008968:Molecular Conformation; D003473:Neuromuscular Nondepolarizing Agents / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D014403:Tubocurarine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004365:Drugs, Chinese Herbal; D008024:Ligands; D003473:Neuromuscular Nondepolarizing Agents; D005711:Gallopamil; D002118:Calcium; C032943:metocurine; D014403:Tubocurarine