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

The identification and structural determination of the critical amino acid residues causing the calcium channel blocking effects of the angusticeps type III toxin FS2 is described. Alignments with more than 200 different short and long neuro-, cyto-, muscarinic and other angusticeps-type toxins yielded 12 amino acid residues at the tips of loops II and III which are unique to the type III toxins. The competitive binding behaviour between the 1,4-dihydropyridine derivative nifedipine and toxin FS2 was used for a further delimitation of the relevant toxin binding domain. Using the ab initio geometry optimized nifedipine X-ray structure as a template, a model based on the sequence Met45-Trp46-cis-Pro47-Tyr48 has been elaborated. This sequence shows the same hydrophobic and hydrogen bond forming properties as nifedipine. In addition, qualitatively similar molecular electrostatic potentials are observed for both structures, leading to the assumption that these amino acid residues of the toxin act as the potential attachment region at the calcium channel receptor site.