Targeting Glycogen Synthase Kinase-3 (Gsk3β) With Naturally Occurring Phytochemicals (Quercetin and its Modelled Analogue): A Pharmacophore Modelling and Molecular Docking Approach

Abstract

Molecular simulation is a significant tool in drug design and modelling. This work consists of a computational analysis through pharmacophore modelling and molecular docking techniques in order to predict the potential inhibitory activity of quercetin and its analogue.  The quercetin analogue QUT1, QUT2, QUT3, QUT4, QUT5, QUT6, QUT7, Quercetin, QUT8, QUT9 and QUT10 were noticed to have minimum energy values of -6.3 kcal/mol, -5.7 kcal/mol, -5.5 kcal/mol, -5.4 kcal/mol, -5.3 kcal/mol, -5.2 kcal/mol, -5.2 kcal/mol, -5.2 kcal/mol, -5.1 kcal/mol,, -5.0 kcal/mol, and +3.0 kcal/mol respectively.  Hence, QUT1 (7-(2,3-dihydroxycyclopropyl)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-4H-1-benzopyran-4-one) was selected as the lead molecule.  The ligand-receptor interaction study of the lead molecule revealed that QUT1 interacted with 15 amino acid residues (CYS 199, ALA 83, LEU 132, ASP 133, TYR 134, VAL 135, PRO 136, THR 138, ARG 141, ILE 62, VAL 61, VAL 110, VAL 70, GLN 72 and LEU 188 ) within the pocket of glycogen synthase kinase-3β.  With favourable ADME prediction of the lead molecule, is possible to conclude that 7-(2,3-dihydroxycyclopropyl)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-4H-1-benzopyran-4-one is a probable drug candidate for any disease in which synthase kinase-3β plays a key role in its cell replication.