کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6451319 | 1416279 | 2017 | 14 صفحه PDF | دانلود رایگان |
- Postulated the possible modes of anthelminthic activity and its underlying resistance mechanisms.
- Identification of three interaction zone of colchicine binding domain of H. contortus β-tubulin homology model using protein-ligand interaction fingerprints.
- Zone-2 anthelmintic structure-based pharmacophore models proposed using dock conformations of β-tubulin anthelmintics and inhibitors.
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 â1 to â3) 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 ± 0.44 à . Further, an aliphatic or a heterocyclic group distant (11.75 ± 1.14 à ) 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.
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Journal: Computational Biology and Chemistry - Volume 68, June 2017, Pages 78-91