New leads for selective GSK-3 inhibition: pharmacophore mapping and virtual screening studies.

Journal of Computer-aided Molecular Design
Dhilon S Patel, Prasad V Bharatam

Abstract

Glycogen Synthase Kinase-3 is a regulatory serine/threonine kinase, which is being targeted for the treatment of a number of human diseases including type-2 diabetes mellitus, neurodegenerative diseases, cancer and chronic inflammation. Selective GSK-3 inhibition is an important requirement owing to the possibility of side effects arising from other kinases. A pharmacophore mapping strategy is employed in this work to identify new leads for selective GSK-3 inhibition. Ligands known to show selective GSK-3 inhibition were employed in generating a pharmacophore map using distance comparison method (DISCO). The derived pharmacophore map was validated using (i) important interactions involved in selective GSK-3 inhibitions, and (ii) an in-house database containing different classes of GSK-3 selective, non-selective and inactive molecules. New Lead identification was carried out by performing virtual screening using validated pharmacophoric query and three chemical databases namely NCI, Maybridge and Leadquest. Further data reduction was carried out by employing virtual filters based on (i) Lipinski's rule of 5 (ii) van der Waals bumps and (iii) restricting the number of rotatable bonds to seven. Final screening was carried out usin...Continue Reading

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Citations

Oct 8, 2008·Journal of Computer-aided Molecular Design·Sivaprakasam PrasannaRobert J Doerksen
Oct 5, 2006·Journal of Molecular Graphics & Modelling·Nigus DessalewPrasad V Bharatam
Oct 26, 2006·Chemical Biology & Drug Design·Nigus Dessalew, Prasad V Bharatam
Sep 6, 2014·Journal of Pathology Informatics·Heidi D NelsonDonald L Weaver

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