Discovery of potent anticonvulsant ligands as dual NMDA and AMPA receptors antagonists by molecular modelling studies

作者：Jain Shailesh V^*; Bhadoriya Kamlendra S; Bari Sanjaykumar B; Sahu Nitendra K; Ghate Manjunath

来源：Medicinal Chemistry Research, 2012, 21(11): 3465-3484.

DOI：10.1007/s00044-011-9889-5

• Aminobenzothiazole
• 2D and 3D-QSAR
• Pharmacophore
• Virtual screening
• Gly/NMDA receptor
• AMPA receptor

To identify novel and potent anticonvulsant ligands, initially 2D and 3D-QSAR models were generated using a series some prop-2-eneamido and 1-acetyl-pyrazolin derivatives of aminobenzothiazole as anticonvulsants. Both the QSAR models yielded significant cross-validated q (2) values of 0.67 and 0.81 and predicted r (2) (pred_r (2)) values of 0.66 and 0.83 for 2D and 3D, respectively. Continuing with series of aminobenzothiazole derivatives chemical feature based pharmacophore models with lowest RMSD value (0.1294 ), consists of two aromatic carbon centre, one hydrogen bond acceptor and one hydrogen bond donor features was developed. To discover new hits, developed pharmacophore model was subjected to screen molecules from specs database. Screened hits which were showing good predicting activities according to both 2D and 3D-QSAR models were subjected to docking screening. Gly/NMDA and AMPA receptors are effective and validated anti-convulsant targets and used to report the binding affinity of screened hit on Gly/NMDA, AMPA receptors. A representative set of 14 compounds with effective biological activity and good binding affinity on both NMDA and AMPA receptors were screen out which may potential lead for anticonvulsant activity.
Four point pharmacophore model of aminobenzothiazole derivatives was developed and screened out novel and potent anticonvulsant ligands using virtual screening technique.

• 出版日期2012-11