Computational approaches guiding for the design and optimization of novel chemo-types endowed with F508del-CFTR modulator ability

To date, monotherapy with VX-809 (Lumacaftor) or VX-770 (Ivacaftor) has not resulted in obvious clinical benefits for CF patients, while their combination regimen has provided positive results, stabilizing disease progress. Consequently, therapy combined with dual modulators or triple combination represents today the most promising prospect for developing new therapies. In this context, the research group in which I have been carrying out this thesis has dealt with rational design and computational studies of CFTR modulators during the past few years. The information obtained from our previous studies allowed us to proceed with the rational design and to predict the possible corrective activity of a new series of compounds with an aminoarylthiazole structure (AAT)1.,165. The previously proposed studies' reliability was supported by biological studies carried out on the newly synthesized molecules in collaboration with the research group led by Dr. Nicoletta Pedemonte (Istituto Giannina Gaslini, Genoa), verifying the corrective activity for F508del-CFTR of the newly designed derivatives. About the computational approaches so far applied, a QSAR model has been developed on the correctors available in literature guiding the following design and synthesis of hybrids compounds. This ligand-based method was used to overcome the paucity of information regarding a single and specific mechanism of action responsible for the corrective activity of VX-809. Indeed, as described in the literature, several hypotheses suggest multiple sites on the CFTR protein to which VX-809 could bind, first of all, the NBD1 domain. This thesis deepened the structure-based approach concerning various correctors described in the literature, including the hybrids developed by the present research group. In this context, experimental but partial data of the NBD1 domain of F508del-CFTR (PDB code: 4WZ6) were considered to perform molecular docking simulations of the compounds mentioned above. This research has been completed by molecular docking calculations performed on a whole model of the F508del-CFTR protein, which has been built in silico by our research group. Unlike what occurs for CFTR correctors, applying structure-based methods in the rational design of potentiators appears to be a more straightforward strategy since the experimental data concerning the binding mode of the VX-770 potentiator has recently become available (PDB code = 6O2P) and GLP1837 (PDB code = 6O1V). Starting from these assumptions, in this thesis, several libraries of compounds, described in the literature as CFTR potentiators, such as indoles, pyrazolquinolines, thienopyranes, cyanoquinolines, and AAT, have been studied to perform molecular docking studies and QSAR analysis activities. These approaches allowed us to obtain information to guide the rational design and future synthesis of new CFTR modulators. The research activity's further goal was to apply - in parallel to the studies just mentioned - ligand-based drug design analysis, using classical QSAR type analysis. This approach made it possible to overcome any limitation related to uniquely examining a single possible target for CFTR modulators and focusing on chemical scaffolds known today as correctors or potentiators.