Computational Studies And Design of Novel Molecules As Potential Glycogen Synthase Kinase Inhibitors

Abstract

The present thesis titled Computational Studies and Design of Novel Molecules as Potential Glycogen Synthase Kinase Inhibitors is divided into 7 chapters as described in brief. newlineChapter 1 describes the disease condition associated with the over expression of GSK-3and#946; enzyme, its structure, various strategies implemented for designing selective GSK-3and#946; inhibitors and clinical status of GSK-3and#946; inhibitors. newlineChapter 2 outlines the aim and objectives of the present work. The aim of the work is to identify new chemical moieties as GSK-3and#946; inhibitors by rational drug design based on in-silico fragment-based and docking approach as well as to identify novel inhibitors via virtual screening of chemical databases. newlineChapter 3 covers detailed literature review of various class of compounds available as GSK-3and#946; inhibitors. They are further classified based on their mode of inhibition as non-ATP competitive, substrate competitive and ATP-competitive GSK-3and#946; inhibitors. A review on patent literature is also covered. newlineChapter 4 describes prediction of binding sites and druggability assessment of GSK-3and#946; by SiteMap software tool. The ligand-binding characteristics and druggability of each site of GSK-3and#946; was assessed with SiteScore (SScore) and Druggability score (Dscore) respectively. Eight sites were identified on the surface of GSK-3and#946;. The ATP-binding site (pocket 1) and allosteric site (pocket 7) were predicted as top scoring sites of GSK-3and#946;. Application of combined in-silico fragment-based and molecular docking approach yielded the design of new chemical series of allosteric pocket 7 targeted N1,3-disubstituted imidazolidin-2-one derivatives. These hits displayed strong H-bond and pi-stacking interactions with Ser236 and His173 residues. newlineApplication of virtual screening methodology based on structural features of Tideglusib; identified new heterocyclic compounds via shape-based similarity screening using ROCS followed by molecular docking, electrostatic similarity search using EON and pharmacophore feature-based searching