The computational repositioning can be considered as a computer analysis for the study of the interaction between drugs already approved for other diseases (drug repurposing) and a therapeutic target. Using High Performance Computing and Surface Plasmon Resonance, the interaction between the three-dimensional model of CFTR-F508deland drugs already in use for CF or other diseases was investigated. These experiments allowed the identification of the natural products rutin, quercin and nicotinamide (NAM) as molecules capable of interacting with the CFTR protein. The researchers also studied the interaction between CFTR and the drug Lumacaftor (VX809) by identifying the binding sites between the drug and the protein. The results obtained from the computational analysis (in-silico) were then validated with a cell model (in-vitro) to evaluate the functionality of the NAM. The researchers report that NAM does not exert any recovery of CFTR when administered alone, but it synergizes the VX809 functionality when administered with the drug. Additional 35 compounds among 13.700 coming from the DrugBank Library were selected by computational repositioning will undergo a biochemical/biological screening to identify other potential drugs.

Pubblications

• Rusnati M, D’Ursi P, Pedemonte N et al. Recent Strategic Advances in CFTR Drug Discovery: An Overview, International Journal of Molecular Sciences, 2020 Apr; 21(7): 2407
• Parodi A, Righetti G, Pesce E et al. Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assay, European Journal of Medicinal Chemistry, Volume 208, 15 December 2020, 112833
• Orro A, Uggeri M, Rusnati M et al. In silico drug repositioning on F508del-CFTR: A proof-of-concept study on the AIFA library, European Journal of Medicinal Chemistry, 2021 Jan 13;213:113186

Congress abstracts

• Uggeri M, Orro A, Urbinati C et al. Rescuing defective CFTR applying a drug repositioning strategy, XXVI National Meeting in Medicinal Chemistry, Milan, Ca’ Granda, July 16-19, 2019