MEF2-HDAC (Class II) Modulators Library

MEF2-HDAC (Class II) Modulators Library

6,400 Compounds

Medicinal and Computational Chemistry Dept., ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121 USA, Service: +1 877 ChemDiv, Tel: +1 858-794-4860, Fax: +1 858-794-4931, Email: [email protected]

Introduction:
The myocyte enhancer factor 2 (MEF2) transcription factor acts as a lynchpin in the transcriptional circuits that control differentiation of diverse cell types including skeletal, cardiac and smooth muscle cells, neurons, chondrocytes, lymphocytes, endothelial cells and neural crest cells. Class II histone deacetylase (HDAC) proteins bind to MEF2 and regulate MEF2 activity in a calcium-dependent manner in response to various signaling cascades.
The crystal structure of a HDAC9/MEF2/DNA complex reveals that HDAC9 binds to a hydrophobic groove of the MEF2 dimer.
ChemDiv proposes the new library of MEF2-HDAC (class II) inhibitors/modulators. This library represents a selection of drug-like compounds aimed at modulating protein-protein interaction (PPI) of MEF2 with HDAC 4, 5, 7 or 9 involved in significant physiological processes. Library has been assembled using in house structural biology insight, molecular stimulation-modeling, virtual screening of ChemDiv’s novel chemistries and medicinal chemistry filtering/ranking of the resulting hits. A representative example of a ‘druggable’ ‘hot spots’ included specific topological features of the MEF2-HDAC interaction (e.g. helix- or beta-sheet mimetics).

Important Information Inspired the Library Design

The MEF2-binding motif of HDAC9 binds MEF2 as an amphipathic helix (gray). The hydrophobic face of the helix, composed of Val143, Leu147, Phe150, and Leu151, fits snugly into a hydrophobic groove formed by helix H2 and the central β sheet. At the center of the HDAC9/MEF2 interface, the side chain of Leu147 inserts into a hydrophobic pocket formed by Leu66, Tyr69 and Thr70 of each MEF2 monomer. The long aliphatic side-chains of polar resides surrounding Leu147, including Lys144, Lys146 and Gln148, also make extensive van der Waals contacts to MEF2. The interface is largely hydrophobic and the intimate surface complementarity is likely the main source of binding specificity

Variable statistics for 7,932 compounds from MEF2_HDAC library.

Diversity 0,7397
The number of screens in dataset 2085
Number of unique heterocycles 82
The number of Scaffolds 83
Singletons 0
Novelty: The number of compounds synthesized (%) per year

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