Pharmacophore modeling, quantitative structure-activity relationship analysis, and in silico screening reveal potent glycogen synthase kinase-3beta inhibitory activities for cimetidine, hydroxychloroquine, and gemifloxacin.
The pharmacophoric space of glycogen synthase kinase-3beta (GSK-3beta) was explored using two diverse sets of inhibitors. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophores and physicochemical descriptors that access self-consistent and predictive quantitative structure-activity relationship (QSAR) against 132 training compounds ( r (2) 123 = 0.663, F = 24.6, r (2) LOO = 0.592, r (2) PRESS against 29 external test inhibitors = 0.695). Two orthogonal pharmacophores emerged in the QSAR, suggesting the existence of at least two distinct binding modes accessible to ligands within GSK-3beta binding pocket. The validity of the QSAR equation and the associated pharmacophores was established by the identification of three nanomolar GSK-3beta inhibitors retrieved from our in-house-built structural database of established drugs, namely, hydroxychloroquine, cimetidine, and gemifloxacin. Docking studies supported the binding modes suggested by the pharmacophore/QSAR analysis. In addition to being excellent leads for subsequent optimization, the anti-GSK-3beta activities of these drugs should have significant clinical implications.
Taha
Mutasem O
MO
Department of Pharmaceutical Sciences and Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, University of Jordan, Amman, Jordan. mutasem@ju.edu.jo
Bustanji
Yasser
Y
Al-Ghussein
Mohamed A S
MA
Mohammad
Mohammad
M
Zalloum
Hiba
H
Al-Masri
Ihab M
IM
Atallah
Naji
N
D000465:Algorithms; D001665:Binding Sites; D002927:Cimetidine / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology*; D000077735:Gemifloxacin; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006886:Hydroxychloroquine / Q000737:chemistry / Q000494:pharmacology*; D016014:Linear Models; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D020539:Sequence Analysis, Protein / Q000379:methods; D012984:Software
D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D009287:Naphthyridines; D006886:Hydroxychloroquine; D002927:Cimetidine; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000077735:Gemifloxacin