The botulinum neurotoxins [BoNT] can be subdivided into immunologically distinct serotypes A-G and are multidomain proteins that are released by pathogenic strains of Clostridium botulinum. Each neurotoxin contains a catalytic domain that is a metalloprotease and cleaves a specific site on one of three proteins involved in synaptic vesicle fusion. Substrate cleavage leads to loss of neurotransmitter release and thus to paralysis, a common symptom in the disease botulism. In this article we have provided an extensive literature review of BoNT structure and function, as well as homology modeling and docking methods. Building upon the known three-dimensional structures of BoNT / A and BoNT / B, we have generated 3D homology models for the catalytic domains of the remaining serotypes. The models, along with the known BoNT / A and BoNT / B crystal structures, have been used in molecular docking experiments using AutoDock to predict binding of five small molecules that are known as weak inhibitors of BoNTs. These docking calculations have been discussed in relation to recent free energy calculations on a BoNT-peptide complex as well as with regard to the known substrate specificity of the seven BoNT serotypes. The results of the docking calculations reveal energetic and structural differences among the BoNT serotypes and provide new information about substrate specificity for future computer-aided drug design efforts to develop more potent BoNT inhibitors.
Keywords: botulin toxin, homology modeling, docking, bioinformatics, metalloprotease, inhibitor, drug design, active site, homology modeling, docking, bioinformatics, metalloprotease, inhibitor, drug design, active site.