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Molecular Chaperones Targeted Library

2 400 compounds

Protein folding is very important as 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 protein families 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 these different chaperones remains largely undefined. Meanwhile, targeting molecular chaperones is proven to be crucial for the prevention of the many deleterious effects of protein misfolding and aggregation, which might lead in the end to cell death, neurodegeneration and other protein misfolding diseases.

Library design

Enamine has been following investigation on molecular chaperones for years and developed a library of 2 400 synthetic compounds potentially targeting molecular chaperones. The emphasis has been placed on 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). In addition, the library was enriched with bioisosteric replacement and compounds bearing new chemotypes predominantly with polar scaffolds and cores to increase novelty of the targeted sets.

The sets of reported active molecules, collected for the targets mentioned above, were carefully analyzed and series of 3D pharmacophore models within volume restriction constraint were created and further validated with the set of reference actives and non-active ligands. Enamine’s MedChem stock compound collection, Ro5 compliant and filtered through series of MedChem filters and rules, was then screened using validated pharmacophore models. The results were evaluated manually and molecules with trivial chemotypes as well as bad matches (e.g. only partly occupied volume, poor pharmacophore) were removed. The bioisosteric replacement of core structures and selection of compounds by privileged motifs were used to enrich the library with valuable new structural fragments and prospective drug/lead-like compounds.

Molecular_Chaperones Molecular_Chaperones Molecular_Chaperones

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.

Molecular_Chaperones

Examples of Enamine’s compounds bearing different chemotypes with representation of known inhibitors structures.

Molecular_Chaperones

Bioisosteric replacement of adenosine core of known highly active molecular chaperones ligands: expansion of structural diversity and chance to improve binding selectivity.

Designed targeted library is a valuable starting point for qualitative Hit finding Projects.



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