4.5 Article

Discovery of KDM5A inhibitors: Homology modeling, virtual screening and structure-activity relationship analysis

Journal

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 9, Pages 2284-2288

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.03.048

Keywords

KDM5A; Histone lysine demethylation; Structure-activity relationship; Epigenetics; Small molecule inhibitor

Funding

  1. National Natural Science Foundation of China [81325021, 81473140, 81573349]
  2. Major State Basic Research Development Program of China [2013CB967204]
  3. PCSIRT [IRT13031]

Ask authors/readers for more resources

Herein we report the discovery of a series of new KDM5A inhibitors. A three-dimensional (3D) structure model of KDM5A jumonji domain was firstly established based on homology modeling. Molecular docking-based virtual screening was then performed against commercial chemical databases. A number of hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the most active hit compound, 9 (IC50: 2.3 mu M), which led to the discovery of several new KDM5A inhibitors. Among them, compound 15e is the most potent one with an IC50 value of 0.22 mu M against KDM5A. This compound showed good selectivity for KDM5A and considerable ability to suppress the demethylation of H3K4me3 in intact cells. Compound 15e could be taken as a good lead compound for further studies. (C) 2016 Published by Elsevier Ltd.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available