Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening |
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| Institution: | 1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA;2. Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA;3. Biochemistry Undergraduate Program, Iowa State University, Ames, IA 50011, USA;4. Simulation Sciences Branch, US Army Research Laboratory, Aberdeen, MD 21005, USA;5. Department of Cell Biology and Biochemistry, USAMRIID, 1425 Porter St., Fort Detrick, MD 21702, USA;6. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;7. Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78227, USA;8. Department of Biochemistry, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA;9. Department of Biophysics, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA;10. Center for Structural Genomics of Infectious Diseases (CSGID), Chicago, IL, USA;11. Biochemistry Graduate Program, Iowa State University, Ames, IA 50011, USA;12. National Magnetic Resonance Facility at Madison, University of Wisconsin, Madison, 433 Babcock Drive, Madison, WI 53706, USA |
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| 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 thieno3,2-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. |
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| Keywords: | Alzheimer’s disease CDK5/p25 inhibitor ATP non-competitive Virtual screening E-pharmacophore |
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