New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach.

Giada Righetti,Michele Tonelli,Elena Cichero,Enrico Millo,Monica Casale,Nicoletta Pedemonte,Paola Fossa,Nara Liessi

doi:10.3390/ph13120445

Abstract

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. Combination therapy with the two series of drugs led to the approval of several multi-drug effective treatments, such as Orkambi, and to the recent promising evaluation of the triple-combination Elexacaftor-Tezacaftor-Ivacaftor. This scenario enlightened the effectiveness of the multi-drug approach to pave the way for the discovery of novel therapeutic agents to contrast CF. The recent X-crystallographic data about the human CFTR in complex with the well-known potentiator Ivacaftor (VX-770) opened the possibility to apply a computational study aimed to explore the key features involved in the potentiator binding. Herein, we discussed molecular docking studies performed onto the chemotypes so far discussed in the literature as CFTR potentiator, reporting the most relevant interactions responsible for their mechanism of action, involving Van der Waals interactions and π–π stacking with F236, Y304, F305 and F312, as well as H-bonding F931, Y304, S308 and R933. This kind of positioning will stabilize the effective potentiator at the CFTR channel. These data have been accompanied by pharmacophore analyses, which promoted the design of novel derivatives endowed with a main (hetero)aromatic core connected to proper substituents, featuring H-bonding moieties. A highly predictive quantitative-structure activity relationship (QSAR) model has been developed, giving a cross-validated r2 (r2cv) = 0.74, a non-cross validated r2 (r2ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r2 (r2pred) = 0.86. On the whole, the results are expected to gain useful information to guide the further development and optimization of new CFTR potentiators.

Highlights

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that results from the functional deficiency in a plasma membrane anion channel known as the cystic fibrosis transmembrane conductance regulator (CFTR) [1,2,3]
We proceeded with deepening molecular docking studies of different series of F508del CFTR potentiators, featuring variable chemo-types as well as potency trend, with the aim at exploring the most relevant key features turning in more effective potentiators (Supplementary Tables S1–S6)
While a number of cyanoquinolines experienced potentiator activity comparable with that of genistein, several piperidinepyridoindole and pyrazoloquinoline were endowed of 6-fold greater ability than that produced by VX-770 alone based on increased short-circuit current in primary human bronchial epithelial cells [26]

Summary

Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disorder that results from the functional deficiency in a plasma membrane anion channel known as the cystic fibrosis transmembrane conductance regulator (CFTR) [1,2,3]. CFTR is a member of the ABC transporter ATPase family and allows for the transmembrane chloride ions to flow down the electrochemical gradient [4,5]. Defective function of this channel can be caused by a variety of mutations, grouped in six classes according to the mechanism through which they cause loss of function [6]. The most frequent class III mutation is G551D [7,8]

Methods

Results

Discussion

Conclusion