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Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking

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Abstract

Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer’s disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3α inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3α and GSK-3β isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the β isoform are the same in the α isoform, except that Asp133 in the β isoform is replaced by Glu196 in the α isoform. We prepared a homology model for GSK-3α, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the β isoform, and helped to explain the difference in their inhibitory activity.

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Acknowledgements

Funding from University of Mississippi, including from its Faculty Research Program and from the Office of Research and Sponsored Programs; from the National Center for Zoonotic, Vector-borne, and Enteric Diseases (CK) of the Centers for Disease Control and Prevention (U01/CI000211); from National Science Foundation (EPS-0556308); and from National Institutes of Health’s National Center for Research Resources (P20 RR021929); as well as Laboratory for Applied Drug Design and Synthesis and MCSR computing facilities are greatly appreciated. SP is a Natural Products Neuroscience Fellow. This investigation was conducted in a facility constructed with support from research facilities improvement program C06 RR-14503-01 from the NIH National Center for Research Resources.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS, 38677-1848, USA

    Sivaprakasam Prasanna, Pankaj R. Daga, Aihua Xie & Robert J. Doerksen

  2. Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, 38677-1848, USA

    Robert J. Doerksen

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  1. Sivaprakasam Prasanna
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Correspondence to Robert J. Doerksen.

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Prasanna, S., Daga, P.R., Xie, A. et al. Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking. J Comput Aided Mol Des 23, 113–127 (2009). https://doi.org/10.1007/s10822-008-9244-1

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