New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach
Autor: | Monica Casale, Enrico Millo, Nara Liessi, Michele Tonelli, Giada Righetti, Paola Fossa, Elena Cichero, Nicoletta Pedemonte |
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Rok vydání: | 2020 |
Předmět: |
Quantitative structure–activity relationship
pharmacophore analyses lcsh:Medicine lcsh:RS1-441 Pharmaceutical Science Computational biology VX-770 Article lcsh:Pharmacy and materia medica Ivacaftor 03 medical and health sciences 0302 clinical medicine CFTR modulator CFTR potentiators F508del CFTR Molecular docking Pharmacophore analyses Drug Discovery medicine F508del cftr CFTR Potentiator 030304 developmental biology 0303 health sciences biology Chemistry lcsh:R molecular docking Potentiator Cystic fibrosis transmembrane conductance regulator Mechanism of action 030220 oncology & carcinogenesis biology.protein Molecular Medicine medicine.symptom Pharmacophore medicine.drug |
Zdroj: | Pharmaceuticals Volume 13 Issue 12 Pharmaceuticals, Vol 13, Iss 445, p 445 (2020) |
ISSN: | 1424-8247 |
Popis: | 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 &pi &ndash &pi 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. |
Databáze: | OpenAIRE |
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