Molecular Chaperones Library
A set of compounds focused on targeting molecular chaperones
2 468 compounds
Protein folding is very important as attractive field in new drug development paradigm. Control of these processes in the cell achieves 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 in cell death, in neurodegeneration and in other protein misfolding diseases.
Enamine has been following investigation on molecular chaperones for years and developed a library of 2 468 synthetic compounds potentially targeted molecular chaperones. The emphasis has been made 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 library is available in convenient and ready to ship pre-plated formats. Also, the library can be delivered in any other custom formats within a week only.
2 468 8 plates
≤ 300 nL of 2 mM solutions in DMSO
384-well micro plates, Greiner Cat. No. 784201; 320 compounds per plate 1, 2 & 23, 24 columns empty
2 468 8 plates
10 µL of 10 mM DMSO stock solutions
384-well microplates, Echo Qualified, 320 compounds per plate, first two and last two columns empty
2 468 31 plates
50 µL of 10 mM DMSO solutions
96-well plates, Greiner No. 650201, 80 compounds per plate, 1& 12 columns empty
- Ligand based approach: pharmacophore searches, bioisosteric replacement, 3D shape-based screening.
- Protein/target-based: Docking, in silico screening with protein-ligand key interaction feature constraints.
- Strict MedChem filters including PAINS and other industry affiliated structural filters and rules.
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.