Conformational analysis of free and Ca(2+)-bound forms of verapamil and methoxyverapamil.

In a recent experimental study (Tetreault, S. and Ananthanarayanan, V.S. (1993) J. Med. Chem. 36, 1324-1332) we showed that verapamil can bind Ca2+ in a nonpolar medium to form 1:1 and 2:1 drug:Ca2+ complexes and proposed that such complexes may represent the bioactive form of the drug. A similar suggestion has also been made earlier from theoretical considerations of the geometry of the drug (Zhorov, B. and Govyrin, V. (1983), Dokl.Akad.Nauk SSSR 273, 497-501). In order to fully understand the nature of the drug-Ca2+ complex, we present in this paper a systematic conformational analysis of the protonated and neutral forms of verapamil and one of its potent analogues, methoxyverapamil (D600). For each form of verapamil and D600, the energies and generalized coordinates of all minimum-energy conformations (MECs) with the energy less than 5 kcal/mol above the global minimum have been accumulated and sorted in the order of increasing energies. A protocol was then used to search in the files MECs meeting a set of geometrical criteria and to sum up their populations. The geometrical criteria involved the predisposition of the oxygen and nitrogen atoms of the drug molecule to form bi- tri- and tetradentate complexes with Ca2+. Use of these criteria demonstrated that both verapamil and D600 have several low-energy structural patterns that are predisposed for bi- and polydentate chelation of Ca2+. Models of various types of 1:1 drug:Ca2+ complexes as well as two models of 2:1 drug:Ca2+ "sandwich" complex were obtained. Such models may be biologically relevant in understanding the nature of the ternary complex formed by the drug, Ca2+ and the calcium channel.