Exploration of interaction zones of β-tubulin colchicine binding domain of helminths and binding mechanism of anthelmintics

Numerous studies postulated the possible modes of anthelmintic activity by targeting alternate or extended regions of colchicine binding domain of helminth beta-tubulin. We present three interaction zones (zones vide 1 to 3) in the colchicine binding domain of Haemonchus contortus (a helminth) beta-tubulin homology model and developed zone-wise structure-based pharmacophore models coupled with molecular docking technique to unveil the binding hypotheses. The resulted ten structure-based hypotheses were then refined to essential three point pharmacophore features that captured recurring and crucial non-covalent receptor contacts and proposed three characteristics necessary for optimal zone-2 binding: a conserved pair of H bond acceptor (HBA to form H bond with Asn226 residue) and an aliphatic moiety of molecule separated by 3.75 +/- 0.44 angstrom. Further, an aliphatic or a heterocyclic group distant (11.75 +/- 1.14 angstrom) to the conserved aliphatic site formed the third feature component in the zone-2 specific anthelmintic pharmacophore model. Alternatively, an additional HBA can be substituted as a third component to establish H bonding with Asn204. We discern that selective zone-2 anthelmintics can be designed effectively by closely adapting the pharmacophore feature patterns and its geometrical constraints. (C) 2017 Elsevier Ltd. All rights reserved.