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Filename: drivers/Session_files_driver.php
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Filename: Session/Session.php
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File: /var/www/html/index.php
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Function: require_once
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Filename: controllers/Detail.php
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Line: 249
Function: _error_handler
File: /var/www/html/index.php
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Function: require_once
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 249
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File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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Function: _error_handler
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Filename: models/Detail_model.php
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File: /var/www/html/application/models/Detail_model.php
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Function: strpos
File: /var/www/html/application/controllers/Detail.php
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Function: insertAPISummary
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Filename: helpers/my_audit_helper.php
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File: /var/www/html/application/helpers/my_audit_helper.php
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Function: str_replace
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Function: formatAIDetailSummary
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Filename: controllers/Detail.php
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Filename: controllers/Detail.php
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Filename: controllers/Detail.php
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Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d-mannosides leads to compounds with perfect π-π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar K values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as H, N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.
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http://dx.doi.org/10.1002/cmdc.201900051 | DOI Listing |
RSC Med Chem
November 2024
Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville Edwardsville IL 62026 USA
Somatostatin receptor-4 (SST) is a therapeutic target for several conditions, including Alzheimer's disease, seizures, neuropsychiatric disorders, and pain. Our previous work on 1,2,4-triazole derivatives led to enhanced SST binding affinity, selectivity, and functional activity. Herein we report the discovery of 3-thio-1,2,4-triazole series as selective and high affinity SST agonists.
View Article and Find Full Text PDFNeurotherapeutics
December 2024
Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Canada. Electronic address:
Positron emission tomography (PET) is a highly sensitive, quantitative imaging technique that can track sub-nanomolar quantities of positron-emitting radionuclides throughout the body. By incorporating such radionuclides into molecules of interest, we can directly assess their pharmacokinetic and pharmacodynamic (PK/PD) characteristics in vivo without changing their physicochemical characteristics or eliciting a pharmacological response. As such, PET imaging has long been used as a tool to aid drug discovery programs from preclinical biomarker validation all the way through to clinical trials.
View Article and Find Full Text PDFBioorg Med Chem Lett
February 2025
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address:
We synthesized and evaluated a series of derivatives based on the pyrimidine-2,4-diamine scaffold as potential JNK1 inhibitors, incorporating bridging rings and spirocyclic modifications to enhance their inhibitory activity. These compounds were biologically assessed through JNK enzyme inhibition assays and Western Blot analysis. Compounds 13, 14 and 19 demonstrated significant inhibitory activity at both the enzyme and cellular level compared to the lead compound 1 and clinical candidate CC-90001.
View Article and Find Full Text PDFAntiviral Res
November 2024
Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address:
bioRxiv
November 2024
Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
The development of macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource-intensive and provide little control over binding mode. Despite considerable progress in physics-based methods for peptide design and deep-learning methods for protein design, there are currently no robust approaches for design of protein-binding macrocycles. Here, we introduce RFpeptides, a denoising diffusion-based pipeline for designing macrocyclic peptide binders against protein targets of interest.
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