Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening. 2543 65

The aim of this work was to investigate the biomolecular targets for a library of indolizines, study their molecular properties, drug likeness, target prediction, performing docking studies and exploring their ADMET profile in search for a lead compound. All compounds appeared to comply with Lipinski's rule without any violation, additionally their solubility is viewed good except for compounds 4a-c which are anticipated to be reasonably soluble, their Milog P score was 4.18-4.9, proposing that these compounds are the most lipophilic with least water solubility, however this may be helpful as the cannabinoid receptor-1 is the most probable target for these three compounds. The inclusive target for the selected library was tau protein. Structure based studies demonstrated great fitting of indolizines with tau protein, along these lines they are expected to have pharmacological action in vivo. This urged us to think about the ADMET properties of this library. These investigations suggested the ability of the selected compounds to pass the blood brain barrier (BBB) (aside from them compounds 2c and 3c) and affect tau proteins, which will be valuable for the treatment of Alzheimer's disease, particularly compound 5 which does not require any SAR modifications to attain the BBB.
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PMID:Drug likeness, targets, molecular docking and ADMET studies for some indolizine derivatives. 3039 81