Scouting new molecular targets for CFTR therapy: the HSC70/BAG-1 complex. A computational study
- First Online:
- 154 Downloads
HSC70 has been identified as an important molecular target involved in the ΔF508-CFTR cystic fibrosis. HSC70 associates ΔF508-CFTR to a much greater extent than WT-CFTR and after this step, it recruits other co-chaperones (BAG1, CHIP) and performs the ubiquitination and proteosomal degradation of the protein. Up to now, several X-ray data concerning the HSC70:BAG1 complexes are available. Thus, we performed an “in silico” investigation focused to explore which different amino acid residues are involved in the binding of ATP, the natural substrate, and the co-crystallized ligands at the HSC70/BAG-1 interface. The study allowed us to evaluate sildenafil and KM11060, which proved to be also CFTR correctors, as potential HSC70:BAG1 inhibitors, and also let us derive interesting perspectives for the development of new CFTR correctors.
KeywordsCFTR HSC70 BAG-1 Computational study
- Macias AT, Williamson DS, Allen N, Borgognoni J, Clay A, Daniels Z, Dokurno P, Drysdale MJ, Francis GL, Graham CJ, Howes R, Matassova N, Murray JB, Parsons R, Shaw T, Surgenor AE, Terry L, Wang Y, Wood M, Massey AJ (2011) Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity. J Med Chem 54:4034–4041PubMedCrossRefGoogle Scholar
- Williamson DS, Borgognoni J, Clay A, Daniels Z, Dokurno P, Drysdale MJ, Foloppe N, Francis GL, Graham CJ, Howes R, Macias AT, Murray JB, Parsons R, Shaw T, Surgenor AE, Terry L, Wang Y, Wood M, Massey AJ (2009) Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J Med Chem 52:1510–1513PubMedCrossRefGoogle Scholar