CREB-binding protein (CREBBP, CBP) is a transcriptional coactivator of a broad range of transcription factors. CBP provides a platform for the assembly of enhanceosomes consisting of a numerous DNA-binding proteins that position the complex in a sterically correct way at promoters. Therefore, CBP functions as a signal integrator for multiple transduction pathways at the level of gene activation, modulating cell growth, differentiation, homeostasis, and viral pathogenesis.
CBP loss of function was demonstrated to play a crucial role in the development of several neurodegenerative pathologies including polyglutamine diseases, spinocerebellar ataxia type 7, and spinal and bulbar muscular atrophy. The defects in CBP have been associated with Rubinstein-Taybi syndrome. Also, CBP has oncogenic potential in prostate cancer, leukemia, melanoma, lung cancer and others.
OTAVA offers new CBP focused library containing 655 compounds. For design of this receptor-based library was used crystal structure of human CBP in complex with dihydroquinoxalinone (resolution 1,10 Å). The bromodomain of CBP was taken for molecular docking. During the docking, a hydrogen bond constraint between docked ligand and side chain of key residue Asn1168 has been set. To filter molecular complexes obtained with the docking, a scoring function cutoff was used. Finally, the complexes retained after the filtering were subjected to visual analysis in order to discard ligands with improper binding mode.
This library comprises drug-like compounds only and provides an excellent basis for epigenetic drug discovery.