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

Main Article Content

Amaku James Friday
Victor Okezie Ikpeazu
Ifeanyi Otuokere
Kalu K. Igwe


Communication in Physical Sciences 2020, 5(4): 497-508

Received 25 June 2020/Accepted 29 July 2020

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.


Download data is not yet available.

Article Details

Author Biographies

Amaku James Friday, Michael Okpara University of Agriculture, Umudike, Abia State Nigeria

Department of Chemistry

Victor Okezie Ikpeazu, Abia State University, Abia State

Department of Biochemistry

Ifeanyi Otuokere , Michael Okpara University of Agriculture, Umudike, Abia State Nigeria

Department of Chemistry

Kalu K. Igwe , Michael Okpara University of Agriculture, Umudike, Abia State, Nigeria.

Departmemt of Veterinary Physiology, Pharmacology and Biochemistry


lonso, M., & Martinez, A. (2004). GSK-3 inhibitors: discoveries and developments. Current MedicinalChemistry, 11, 6, pp. 755-763.

Babu, K. S., Babu, T. H., Srinivas, P., Kishore, K. H., Murthy, U., & Rao, J. M. (2006). Synthesis and biological evaluation of novel C (7) modified chrysin analogues as antibacterial agents. Bioorganic & medicinal chemistry letters, 16, 1, pp. 221-224.

Chan, E. C., Pannangpetch, P., & Woodman, O. L. (2000). Relaxation to flavones and flavonols in rat isolated thoracic aorta: mechanism of action and structure-activity relationships. Journal of cardiovascular pharmacology,35, 2, pp. 326-333.

Cho, H., Yun, C.-W., Park, W.-K., Kong, J.-Y., Kim, K. S., Park, Y., Kim, B.-K. (2004). Modulation of the activity of pro-inflammatory enzymes, COX-2 and iNOS, by chrysin derivatives. Pharmacological Research,49, 1, pp. 37-43.

Cos, P., Vlietinck, A. J., Berghe, D. V., & Maes, L. (2006). Anti-infective potential of natural products: how to develop a stronger in vitro ‘proof-of-concept’. Journal of ethnopharmacology, 106, 3, pp. 290-302.

Davis, J. M., Murphy, E. A., & Carmichael, M. D. (2009). Effects of the dietary flavonoid quercetin upon performance and health. Current sports medicine reports,8, 4, pp. 206-213.

Dorronsoro, I., Castro, A., & Martinez, A. (2002). Inhibitors of glycogen synthase kinase-3: future therapy for unmet medical needs? Expert Opinion on Therapeutic Patents, 12, 10, pp. 1527-1536.

Embi, N., Rylatt, D. B., & Cohen, P. (1980). Glycogen Synthase Kinase‐3 from Rabbit Skeletal Muscle: Separation from Cyclic‐AMP‐Dependent Protein Kinase and Phosphorylase Kinase. European Journal of biochemistry,10, 2, pp. 519-527.

Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. (2012). Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of cheminformatics, 4, 1, pp. 17,

Hollman, P. C., Bijsman, M. N., Van Gameren, Y., Cnossen, E. P., De Vries, J. H., & Katan, M. B. (1999). The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man. Free radical research, 31, 6, pp. 569-573.

Lee, J., Kim, Y., Lee, C., Lee, H., & Han, S. (1999). Use of flavones, coumarins and related compounds to treat infections. Saengyak Hakhoe Chi, 30, pp. 34-39.

Martinez, A., Castro, A., Dorronsoro, I., & Alonso, M. (2002). Glycogen synthase kinase 3 (GSK‐3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Medicinal research reviews, 22, 4, pp. 373-384.

Morris, G. M., Goodsell, D. S., Halliday, R. S., Huey, R., Hart, W. E., Belew, R. K., & Olson, A. J. (1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. Journal of computational chemistry, 19, 14, pp. 1639-1662.

Pandiyan, R., & Ilango, K. (2020). Isolation, characterization, and validation of RP-HPLC method for the quantification of quercetin in

Huberantha senjiana leaf extract. Journal of Applied Pharmaceutical Science, 10, 05, pp. 110-118.

Patwardhan, B., Vaidya, A. D., & Chorghade, M. (2004). Ayurveda and natural products drug discovery. Current science, pp. 789-799.

Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—a visualization system for exploratory research and analysis. Journal of computational chemistry, 25, 13, pp. 1605-1612.

Ramachandran, M., Narasimhan, D., & Balachandran, N. (2015). A new species of Hubera (Annonaceae) from Peninsular India. Phytotaxa, 207, 1, pp. 129-134.

Ross, J. A., & Kasum, C. M. (2002). Dietary flavonoids: bioavailability, metabolic effects, and safety. Annual review of Nutrition, 22, 1, pp. 19-34.

T Ramesha, B., Gertsch, J., Ravikanth, G., Priti, V., N Ganeshaiah, K., & Uma Shaanker, R. (2011). Biodiversity and chemodiversity: future perspectives in bioprospecting. Current drug targets, 12, 11, pp. 1515-1530.

Woodman, O. L., & Chan, E. C. (2004). Vascular and anti‐oxidant actions of flavonols and flavones. Clinical and Experimental Pharmacology and Physiology, 31, 11, pp. 786-790.

Zanoli, P., Avallone, R., & Baraldi, M. (2000). Behavioral characterisation of the flavonoids apigenin and chrysin. Fitoterapia, 71, pp. S117-S123.