title: Exploration of interaction zones of β-tubulin colchicine binding domain of helminths and binding mechanism of anthelmintics.
abstract: Numerous studies postulated the possible modes of anthelmintic activity by targeting alternate or extended regions of colchicine binding domain of helminth β-tubulin. We present three interaction zones (zones vide -1 to -3) in the colchicine binding domain of Haemonchus contortus (a helminth) β-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±0.44Å. Further, an aliphatic or a heterocyclic group distant (11.75±1.14Å) 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.
authors.affiliation: School of Chemical Sciences, Central University of Gujarat, Sector-30, Gandhinagar, 382030, Gujarat, India.
authors.forename: Prabodh
authors.initials: P
authors.lastname: Ranjan
authors.affiliation: School of Chemical Sciences, Central University of Gujarat, Sector-30, Gandhinagar, 382030, Gujarat, India.
authors.forename: Sivakumar Prasanth
authors.initials: SP
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, 632014, Tamil Nadu, India.
authors.forename: Vijayakrishna
authors.initials: V
authors.lastname: Kari
authors.affiliation: Centre for Applied Chemistry, Central University of Gujarat, Sector-30, Gandhinagar, 382030, Gujarat, India. Electronic address: prakash.jha@cug.ac.in.
authors.forename: Prakash Chandra
authors.initials: PC
authors.lastname: Jha
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003078:Colchicine / Q000737:chemistry*; D006376:Helminths / Q000737:chemistry* / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D014404:Tubulin / Q000737:chemistry*
chemical_list: D000871:Anthelmintics; D014404:Tubulin; D003078:Colchicine
keywords: Anthelmintics; Colchicine; Docking; Nematode; Pharmacophore; Structure-based model; β-tubulin