Molecular Docking and QSAR Studies as Computational Tools Exploring the Rescue Ability of F508del CFTR Correctors

Abstract

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. Different mutations involving the cystic fibrosis transmembrane regulator protein (CFTR) gene, which encodes the CFTR channel, are involved in CF. A number of life-prolonging therapies have been conceived and deeply investigated to combat this disease. Among them, the administration of the so-called CFTR modulators, such as correctors and potentiators, have led to quite beneficial effects. Recently, based on QSAR (quantitative structure activity relationship) studies, we reported the rational design and synthesis of compound 2, an aminoarylthiazole-VX-809 hybrid derivative exhibiting promising F508del-CFTR corrector ability. Herein, we explored the docking mode of the prototype VX-809 as well as of the aforementioned correctors in order to derive useful guidelines for the rational design of further analogues. In addition, we refined our previous QSAR analysis taking into account our first series of in-house hybrids. This allowed us to optimize the QSAR model based on the chemical structure and the potency profile of hybrids as F508del-CFTR correctors, identifying novel molecular descriptors explaining the SAR of the dataset. This study is expected to speed up the discovery process of novel potent CFTR modulators.

Magnolol and Luteolin Inhibition of α-Glucosidase Activity: Kinetics and Type of Interaction Detected by In Vitro and In Silico Studies

“…This coarse classification of chemical types is used to separate water sites from more likely hydrophobic sites. Afterward, the generation of alpha spheres on these preliminary sites has to be performed by eliminating those that correspond to inaccessible or are too exposed to the solvent regions of the protein [56]. Finally, all collected sites based on hydrophilic/hydrophobic properties are ranked according to their Propensity for Ligand Binding (PLB) score, which is based on the amino acid composition of the pocket [57].…”

NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis

“…Docking calculations were performed considering the X-ray crystallographic data of the NBD2 domain of the CFTR protein downloaded from the protein data bank (PDB code 6UK1; resolution 2.69 Å) [43]. The most probable binding sites within the biological target were detected by means of MOE Site Finder, choosing the best top ranked cavity (namely BS1), using a protocol detailed elsewhere [44]. Finally, all the collected sites based on hydrophilic/hydrophobic properties were ranked according to their Propensity for Ligand Binding (PLB) score, which is based on the amino acid composition of the pocket as described in the literature [45].…”

“…We explored the putative binding mode of the FCG corrector by performing molecular docking calculations at the crystallographic structure of the CFTR NBD2 domain [43]. First, we identified the putative binding site (namely BS1) using the MOE Site Finder module, as described in the experimental section [42][43][44][45][46]. Successively, all the molecular docking studies were focused to the BS1 site.…”

CFTR corrector efficacy is associated with occupancy of distinct binding sites

“…The architecture of this pocket might however depend on the conformational state of the CFTR regulatory (R) domain, which is located immediately downstream NBD1 helix H9. It should be noted here that another binding site was recently proposed for VX-809 and aminoarylthiazole-VX-809 hybrid derivatives, next to the ATP-binding site, in a location similar to the second scoring pose highlighted here by blind docking on the F508del-NBD1 3D structure (53). Whether or not this binding site is also relevant for increasing NBD1 stability and CFTR rescue deserves further investigation.…”