Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 22, Pages 6409-6421Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.09.043
Keywords
Alzheimer's disease; CDK5/p25 inhibitor; ATP non-competitive; Virtual screening; E-pharmacophore
Funding
- National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health (NIH), United States [9P20GM104932]
- NIH National Center for Research Resources [C06RR14503]
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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 noncompetitive CDK5/p25 inhibitors with good CDK2/E selectivity. Published by Elsevier Ltd.
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