Comparative molecular modelling study of the calcium channel blockers nifedipine and black mamba toxin FS2

The identification and structural determination of the criticalamino acid residues causing the calcium channel blocking effects of theangusticeps type III toxin FS₂ is described. Alignments withmore than 200 different short and long neuro-, cyto-, muscarinic and otherangusticeps-type toxins yielded 12 amino acid residues at the tips of loopsII and III which are unique to the type III toxins. The competitive bindingbehaviour between the 1,4-dihydropyridine derivative nifedipine and toxinFS₂ was used for a further delimitation of the relevant toxinbinding domain. Using the ab initio geometry optimized nifedipine X-raystructure as a template, a model based on the sequenceMet⁴⁵-Trp⁴⁶-cis-Pro⁴⁷-Tyr⁴⁸has been elaborated. This sequence shows the same hydrophobic andhydrogen bond forming properties as nifedipine. In addition, qualitativelysimilar molecular electrostatic potentials are observed for both structures,leading to the assumption that these amino acid residues of the toxin act asthe potential attachment region at the calcium channel receptor site.