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Scouting new molecular targets for CFTR therapy: the HSC70/BAG-1 complex. A computational study

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Abstract

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.

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Acknowledgments

This research was supported by Italian Cystic Fibrosis Foundation (Grant FFC#5/2010), with the contribution of Philip Watch–Morellato & Sector Group. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. E.C. was financially supported by a post-doc fellowship, Area Chimica, University of Genova.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV n. 3, 16132, Genoa, Italy

    Elena Cichero, Mauro Mazzei & Paola Fossa

  2. Dipartimento di Scienze Farmaceutiche (FARMABIOMED), Università di Salerno—Via Ponte Don Melillo, 84084, Fisciano, SA, Italy

    Anna Basile & Maria Caterina Turco

  3. Biouniversa Srl, Salerno, Italy

    Anna Basile & Maria Caterina Turco

Authors
  1. Elena Cichero
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  2. Anna Basile
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  3. Maria Caterina Turco
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  4. Mauro Mazzei
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  5. Paola Fossa
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Correspondence to Paola Fossa.

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Cichero, E., Basile, A., Turco, M.C. et al. Scouting new molecular targets for CFTR therapy: the HSC70/BAG-1 complex. A computational study. Med Chem Res 21, 4430–4436 (2012). https://doi.org/10.1007/s00044-012-9985-1

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  • DOI: https://doi.org/10.1007/s00044-012-9985-1

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