Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools

Liessi, Nara; Cichero, Elena; Pesce, Emanuela; Arkel, Maria; Salis, Annalisa; Tomati, Valeria; Paccagnella, Matteo; Damonte, Gianluca; Tasso, Bruno; Galietta, Luis J V; Pedemonte, Nicoletta; Fossa, Paola; Millo, Enrico

doi:10.1016/j.ejmech.2017.12.030

Cited by 30 publications

(40 citation statements)

References 44 publications

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“…F508del is the most frequent CF causing mutation, which leads to the improper folding of the protein and its degradation 127 . Subsequent to the identification, QSAR analysis has further been applied to guide the synthesis of novel compounds to treat CF by improving the trafficking of the mutant CFTR (the CF corrector) 128 . Recent works have collected all compounds known to improve the F508del trafficking and then applied QSAR analysis to indicate the critical chemical descriptors for the potential F508del correctors 128 .…”

Section: Ligand-based Approaches In Drug Designmentioning

confidence: 99%

“…Subsequent to the identification, QSAR analysis has further been applied to guide the synthesis of novel compounds to treat CF by improving the trafficking of the mutant CFTR (the CF corrector) 128 . Recent works have collected all compounds known to improve the F508del trafficking and then applied QSAR analysis to indicate the critical chemical descriptors for the potential F508del correctors 128 . A novel predictive model was then constructed with these identified descriptors to provide further guiding to the design and optimization of novel correctors 128 .…”

Section: Ligand-based Approaches In Drug Designmentioning

confidence: 99%

See 1 more Smart Citation

Structural Perspective on Revealing and Altering Molecular Mechanisms of Genetic Variants Linked with Diseases

Peng¹,

Alexov²,

Basu³

2018

Preprint

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Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It is to be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context to which it occurs. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico-chemical properties of the amino acids (native vs. mutant) can still have minimal effects of protein thermodynamics. However, if a mutation causes significant perturbation of either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize on the effects of mutations on two important biophysical characteristics, stability and binding affinity and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical characteristics.

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Section: Ligand-based Approaches In Drug Designmentioning

confidence: 99%

Section: Ligand-based Approaches In Drug Designmentioning

confidence: 99%

Structural Perspective on Revealing and Altering Molecular Mechanisms of Genetic Variants Linked with Diseases

Peng¹,

Alexov²,

Basu³

2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Molecules 2020, 25, x FOR PEER REVIEW 3 of 34 showed carcinogenic activity and, thus, unsatisfactory results in Phase II clinical trials [13,19]. The prediction of pharmacokinetic, toxicological, and stereo-electronic features by in silico studies would be an interesting way for choosing drugs with inhibitory potential, such as demonstrated in previous studies [17,20,21]. In this way, the present work aims to search for compounds via pharmacophore-based virtual screening procedures.…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

et al. 2020

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Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.

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“…In addition to addressing the disease symptomatically, a personalized medicinal approach targeting the specific protein defect has also been used recently in many studies in the CF field [ 34 , 35 , 36 , 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

Pibiri

Melfi

Tutone

et al. 2020

IJMS

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Cystic fibrosis (CF) patients develop a severe form of the disease when the cystic fibrosis transmembrane conductance regulator (CFTR) gene is affected by nonsense mutations. Nonsense mutations are responsible for the presence of a premature termination codon (PTC) in the mRNA, creating a lack of functional protein. In this context, translational readthrough-inducing drugs (TRIDs) represent a promising approach to correct the basic defect caused by PTCs. By using computational optimization and biological screening, we identified three new small molecules showing high readthrough activity. The activity of these compounds has been verified by evaluating CFTR expression and functionality after treatment with the selected molecules in cells expressing nonsense–CFTR–mRNA. Additionally, the channel functionality was measured by the halide sensitive yellow fluorescent protein (YFP) quenching assay. All three of the new TRIDs displayed high readthrough activity and low toxicity and can be considered for further evaluation as a therapeutic approach toward the second major cause of CF.

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Synthesis and biological evaluation of novel thiazole- VX-809 hybrid derivatives as F508del correctors by QSAR-based filtering tools

Cited by 30 publications

References 44 publications

Structural Perspective on Revealing and Altering Molecular Mechanisms of Genetic Variants Linked with Diseases

Structural Perspective on Revealing and Altering Molecular Mechanisms of Genetic Variants Linked with Diseases

Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

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