18 research outputs found
meso-4,5-Diphenylimidazolidin-2-one
The crystal structure determination of the title compound, C15H14N2O, confirms the cis relationship between the phenyl groups at the 4- and 5-positions on the imidazolidine ring. The dihedral angle between the two phenyl rings is 48.14 (6)°. In the crystal structure, intermolecular N—H⋯O hydrogen bonds link molecules into centrosymmetric dimers. These dimers are, in turn, linked into a two-dimensional network via weak N—H⋯π(arene) interactions and π–π stacking interactions with centroid–centroid distances of 3.6937 (11) Å
Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease
The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of a range of human coronavirus diseases. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant drug repurposing candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.We gratefully acknowledge funding that supported this research support from the Ryerson University Faculty of Science (CNA), as well as funding support in the form of a CIFAR Catalyst Grant (JPJ and CNA), an NSERC Alliance Grant (CNA) and the Ryerson COVID-19 SRC Response Fund award (CNA). BW is partly supported by CIFAR AI Chairs Program. This work was also supported by a Mitacs award (BW), the European Union’s Horizon 2020 research and innovation program under a Marie Sklodowska-Curie grant (ER), by the CIFAR Azrieli Global Scholar program (JPJ), by the Ontario Early Researcher Awards program (JPJ and CNA), and by the Canada Research Chairs program (JPJ). We also thank Dr. James Rini (University of Toronto) for the kind gift of the 9.8E12 antibody used to detect the 229E Spike protein, and Dr. Scott Gray-Owen (University of Toronto) for the kind gift of the NL63 human coronavirus.Peer reviewe
Synthesis and Properties of Molecular Probes for the Rescue Site on Mutant Cystic Fibrosis Transmembrane Conductance Regulator
N,1-Bis(4-chloro-2-methylbenzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide
In the title molecule, C27H26Cl2N2O2, the chloro-substituted benzene rings make dihedral angles of 83.29 (9) and 80.81 (9)° with the benzene ring of the tetrahydroquinoline group. The dihedral angle formed by the two chloro-substituted benzene rings is 40.87 (12)°. The six-membered N-containing ring is in a half-chair conformation. In the crystal structure, intermolecular N—H...O hydrogen bonds link molecules into centrosymmetric dimers
Synthesis and Evaluation of Ivacaftor Derivatives with Reduced Lipophilicity
Mutations in the
unique ATP-binding cassette anion channel, the
cystic fibrosis conductance regulator (CFTR), lead to the inherited
fatal disease known as cystic fibrosis (CF). Ivacaftor enhances channel
gating of CFTR by stabilizing its open state and has been approved
as monotherapy for CF patients with CFTR gating mutations (e.g., G551D)
and as part of combination therapy with lumacaftor for CFTR folding
mutations (e.g., ΔF508). However, in the latter context, ivacaftor
may destabilize folding-rescued ΔF508-CFTR and membrane-associated
proteins and attenuate lumacaftor pharmacotherapy. Here, we tested
the hypothesis that the high lipophilicity of ivacaftor may contribute
to this effect. We describe the synthesis of three glutamic acid ivacaftor
derivatives with reduced lipophilicity that bear different charges
at neutral pH (compounds 2, 3, 4). In a cellular ion flux assay, all three restored G551D-CFTR channel
activity at comparable or better levels than ivacaftor. Furthermore,
unlike ivacaftor, compound 3 did not attenuate levels
of folding-rescued ΔF508 at the cell surface. Molecular modeling
predicts that the increased polarity of compound 3 allows
engagement with polar amino acids present in the binding pocket with
hydrogen bonding and ionic interactions, which are collectively higher
in strength as compared to hydrophobic interactions that stabilize
ivacaftor. Overall, the data suggests that reduced lipophilicity may
improve the efficacy of this class of CFTR potentiators when used
for folding-rescued ΔF508-CFTR
Synthesis and Evaluation of Ivacaftor Derivatives with Reduced Lipophilicity
Mutations in the
unique ATP-binding cassette anion channel, the
cystic fibrosis conductance regulator (CFTR), lead to the inherited
fatal disease known as cystic fibrosis (CF). Ivacaftor enhances channel
gating of CFTR by stabilizing its open state and has been approved
as monotherapy for CF patients with CFTR gating mutations (e.g., G551D)
and as part of combination therapy with lumacaftor for CFTR folding
mutations (e.g., ΔF508). However, in the latter context, ivacaftor
may destabilize folding-rescued ΔF508-CFTR and membrane-associated
proteins and attenuate lumacaftor pharmacotherapy. Here, we tested
the hypothesis that the high lipophilicity of ivacaftor may contribute
to this effect. We describe the synthesis of three glutamic acid ivacaftor
derivatives with reduced lipophilicity that bear different charges
at neutral pH (compounds 2, 3, 4). In a cellular ion flux assay, all three restored G551D-CFTR channel
activity at comparable or better levels than ivacaftor. Furthermore,
unlike ivacaftor, compound 3 did not attenuate levels
of folding-rescued ΔF508 at the cell surface. Molecular modeling
predicts that the increased polarity of compound 3 allows
engagement with polar amino acids present in the binding pocket with
hydrogen bonding and ionic interactions, which are collectively higher
in strength as compared to hydrophobic interactions that stabilize
ivacaftor. Overall, the data suggests that reduced lipophilicity may
improve the efficacy of this class of CFTR potentiators when used
for folding-rescued ΔF508-CFTR
Synthesis and Evaluation of Ivacaftor Derivatives with Reduced Lipophilicity
Mutations in the
unique ATP-binding cassette anion channel, the
cystic fibrosis conductance regulator (CFTR), lead to the inherited
fatal disease known as cystic fibrosis (CF). Ivacaftor enhances channel
gating of CFTR by stabilizing its open state and has been approved
as monotherapy for CF patients with CFTR gating mutations (e.g., G551D)
and as part of combination therapy with lumacaftor for CFTR folding
mutations (e.g., ΔF508). However, in the latter context, ivacaftor
may destabilize folding-rescued ΔF508-CFTR and membrane-associated
proteins and attenuate lumacaftor pharmacotherapy. Here, we tested
the hypothesis that the high lipophilicity of ivacaftor may contribute
to this effect. We describe the synthesis of three glutamic acid ivacaftor
derivatives with reduced lipophilicity that bear different charges
at neutral pH (compounds 2, 3, 4). In a cellular ion flux assay, all three restored G551D-CFTR channel
activity at comparable or better levels than ivacaftor. Furthermore,
unlike ivacaftor, compound 3 did not attenuate levels
of folding-rescued ΔF508 at the cell surface. Molecular modeling
predicts that the increased polarity of compound 3 allows
engagement with polar amino acids present in the binding pocket with
hydrogen bonding and ionic interactions, which are collectively higher
in strength as compared to hydrophobic interactions that stabilize
ivacaftor. Overall, the data suggests that reduced lipophilicity may
improve the efficacy of this class of CFTR potentiators when used
for folding-rescued ΔF508-CFTR