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Article
Discovery of Thienoquinolone Derivatives as Selective and ATP Non-Competitive CDK5/p25 Inhibitors by Structure-Based Virtual Screening
Bioorganic & Medicinal Chemistry
  • Arindam Chatterjee, University of Mississippi
  • Stephen J. Cutler, University of Mississippi
  • Robert J. Doerksen, University of Mississippi
  • Ikhlas A. Khan, University of Mississippi
  • John S. Williamson, University of Dayton
Document Type
Article
Publication Date
11-1-2014
Abstract

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity.

Inclusive pages
6409–6421
ISBN/ISSN
0968-0896
Document Version
Postprint
Comments

The document available for download is the authors' accepted manuscript, provided in compliance with the publisher's policy on self-archiving. Differences may exist between this document and the published version, available using the link provided. Permission documentation is on file.

Publisher
Elsevier
Peer Reviewed
Yes
Citation Information
Arindam Chatterjee, Stephen J. Cutler, Robert J. Doerksen, Ikhlas A. Khan, et al.. "Discovery of Thienoquinolone Derivatives as Selective and ATP Non-Competitive CDK5/p25 Inhibitors by Structure-Based Virtual Screening" Bioorganic & Medicinal Chemistry Vol. 22 Iss. 22 (2014)
Available at: http://0-works.bepress.com.library.simmons.edu/john-williamson/2/