Abstract
Cystic fibrosis (CF) is caused by different mutations related to the cystic fibrosis transmembrane regulator protein (CFTR), with F508del being the most common. Pioneering the development of CFTR modulators, thanks to the development of effective correctors or potentiators, more recent studies deeply encouraged the administration of triple combination therapeutics. However, combinations of molecules interacting with other proteins involved in functionality of the CFTR channel recently arose as a promising approach to address a large rescue of F508del-CFTR. In this context, the design of compounds properly targeting the molecular chaperone Hsp70, such as the allosteric inhibitor MKT-077, proved to be effective for the development of indirect CFTR modulators, endowed with ability to amplify the accumulation of the rescued protein. Herein we performed structure-based studies of a number of allosteric HSP70 inhibitors, considering the recent X-ray crystallographic structure of the human enzyme. This allowed us to point out the main interaction supporting the binding mode of MKT-077, as well as of the related analogues. In particular, cation-π and π–π stacking with the conserve residue Tyr175 deeply stabilized inhibitor binding at the HSP70 cavity. Molecular docking studies had been followed by QSAR analysis and then by virtual screening of aminoaryl thiazoles (I–IIIa) as putative HSP70 inhibitors. Their effectiveness as CFTR modulators has been verified by biological assays, in combination with VX-809, whose positive results confirmed the reliability of the whole applied computational method. Along with this, the “in-silico” prediction of absorption, distribution, metabolism, and excretion (ADME) properties highlighted, once more, that AATs may represent a chemical class to be further investigated for the rational design of novel combination of compounds for CF treatment.
Highlights
Cystic fibrosis (CF) is the autosomal recessive disorder most common in Caucasian populations [1]
Compounds in-silico evaluation of AATs (I–IIIa) had been synthesized based on the chemical synthesis previously described [39], and by exploiting the YFP-based functional assay, we performed a preliminary evaluation of their efficacy in rescuing mutant F508del-cystic fibrosis transmembrane regulator protein (CFTR) trafficking, as single agents or in combination with correctors VX-809 and 7m [41]
We reported, for the first time, structure-based studies related to the putative docking mode of MKT-077, as well as of several analogues described in the literature, considering the recent X-ray crystallographic structure of the human HSP70
Summary
Cystic fibrosis (CF) is the autosomal recessive disorder most common in Caucasian populations [1]. Recent studies, reported in the literature by Young and co-workers [31], pointed out a key role played by allosteric ligands targeting the Hsc70/Hsp proteins to deeply amplify the corrector ability of lumacaftor They shown that the stability barrier of rescued F508del-CFTR can be circumvented by a new combination of mechanisms. Despite its little cytotoxicity against either normal hu of 25 man fibroblasts or immortalized epithelial cells, it was withdrawn by Phase I clinical trials because of poor metabolic stability [35] For this reason, during the last years, a number of studies have been performed to modify the chemical structure of the prototype towards novel compounds maintaining the same HSP70 allosteric modulator ability but exhibiting number of studies have been performed to modify the chemical structure of the prototype a better safety and pharmacokinetic (PK) profile [36,37]. Of a consistent series of MKT-077 analogues that have, so far, been reported in the literaIn this context, we deemed it interesting to better explore the putative binding turemode [36,37]ofas allosteric HSP70 ability inhibit cellular a consistent series ofinhibitors, MKT-077 exhibiting analogues variable that have, so far,tobeen reported in the growth in cancer lines
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