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Asian Journal of Biochemistry

Year: 2006 | Volume: 1 | Issue: 3 | Page No.: 236-243
Research Article

QSAR Studies on Some GSK-3α Inhibitory 6-aryl-pyrazolo (3,4-b) pyridines

Ashutosh Jamloki
Department of Pharmacy, Shri G. S. Institute of Technology and Science, 23 Park Road, Indore-452003, Madhya Pradesh, India
C. Karthikeyan
Department of Pharmacy, Shri G. S. Institute of Technology and Science, 23 Park Road, Indore-452003, Madhya Pradesh, India
S.K. Sharma
Maharaja Surajmal Institute of Pharmacy, New Delhi, India
N.S. Hari Narayana Moorthy
School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Viswavidyalya, Airport Bypass Road, Gandhi Nagar, Bhopal-462036, Madhya Pradesh, India
P. Trivedi
Department of Pharmacy, Shri G. S. Institute of Technology and Science, 23 Park Road, Indore-452003, Madhya Pradesh, India
A quantitative structure-activity relationship study on 6-aryl-pyrazolo (3,4-b) pyridines was performed to gain structural insight into the binding mode of the molecules to the glycogen synthase kinase -3α, an enzyme phosphorylate and inhibit Glycogen Synthase (GS) which is the rate limiting enzyme in the glycogen biosynthesis. The molecular modeling studies were performed using CS Chem. Office 2001 molecular modeling software version 6.0. Allinger`s MM2 force field by fixing Root Mean Square Gradient (RMS) to 0.1 Kcal mol-1 and semiemperical AM1 Hamiltonian method (MOPAC module) were used to minimize the energy and calculate descriptors. The thermodynamic and steric features of 6-aryl-pyrazolo (3,4-b) pyridines are highly correlated with GSK-3α inhibitory activity. The results of the study suggests that introduction of bulky groups at C-5 position of the pyrazolopyridine ring will increase the GSK-3α inhibitory potency as it may involve in hydrophobic interaction with the ATP binding site of the enzyme. The results of the study reveal that the conformational rigidity and orientation of molecule play significant role in the GSK-3α inhibitory activity. Additionally, electronic interactions between molecule and enzyme were found to be crucial for GSK-3α inhibitory activity.
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