Molecular Chaperones Library

A set of compounds targeting molecular chaperones; designed by ligand-based methods

2 468 compounds

Protein folding is very attractive field in new drug development paradigm. Control of these processes in the cell is achieved through action of assembly of enzymes known as molecular chaperones. This set of diverse proteins assists a large variety of processes involving folding, translocation, unfolding, disaggregation and homeostasis of proteins within the cellular environment. In spite of intensive studies, the spectrum of cellular substrates and functions mediated by different chaperones remains largely undefined. Meanwhile, targeting molecular chaperones is proven to be crucial for prevention of many deleterious effects of protein misfolding and aggregation, which might lead to cell death, neurodegeneration and other diseases.

Enamine’s Molecular Chaperones Targeted Library comprises 2 468 synthetic compounds targeting most promising and studied targets: Heat shock proteins (Hsp90, Hsp82, Hsp27), chaperone activity of bc1 complex-like and histone-chaperone ASF1a complex (ASF1-histone interaction).

Library Design

The sets of the reported active molecules, collected for the targets mentioned above, were carefully analyzed. Series of 3D pharmacophore models within volume restriction constraints were created and further validated with the set of reference actives and non-active ligands (Figure 1). Enamine’s MedChem stock compound collection (Ro5 compliant and filtered through series of MedChem filters) was then screened against these models. The results were inspected visually, and molecules derived from trivial chemotypes, as well as those poorly matching the pharmacophore models, were removed. The bioisosteric replacement of the core structures and selection of compounds by privileged motifs were also used to enrich the library with new valuable structures and prospective drug/lead-like compounds.

Figure 1. Examples of 3D pharmacophore models. In the cases when protein 3D structure was known superposition of ligand and protein key features was used to create pharmacophore model.

Examples of the molecules in the library

Bioisosteric replacements of the adenosine core of known highly active molecular chaperones ligands

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