ABSTRACT
Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 µM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint = 15.6 µl/min/mg; T1/2 = 113.2 min) with solubility of 4.82 µM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.
Subject(s)
Drug Design , Enzyme Inhibitors/chemistry , Indoles/chemistry , Phosphoric Diester Hydrolases/chemistry , Administration, Oral , Animals , Binding Sites , Drug Stability , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Half-Life , Humans , Imidazoles/chemistry , Indoles/metabolism , Indoles/pharmacokinetics , Microsomes, Liver/metabolism , Molecular Docking Simulation , Phosphoric Diester Hydrolases/metabolism , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , StereoisomerismABSTRACT
INTRODUCTION: Rumors and conspiracy theories, can contribute to vaccine hesitancy. Monitoring online data related to COVID-19 vaccine candidates can track vaccine misinformation in real-time and assist in negating its impact. This study aimed to examine COVID-19 vaccine rumors and conspiracy theories circulating on online platforms, understand their context, and then review interventions to manage this misinformation and increase vaccine acceptance. METHOD: In June 2020, a multi-disciplinary team was formed to review and collect online rumors and conspiracy theories between 31 December 2019-30 November 2020. Sources included Google, Google Fact Check, Facebook, YouTube, Twitter, fact-checking agency websites, and television and newspaper websites. Quantitative data were extracted, entered in an Excel spreadsheet, and analyzed descriptively using the statistical package R version 4.0.3. We conducted a content analysis of the qualitative information from news articles, online reports and blogs and compared with findings from quantitative data. Based on the fact-checking agency ratings, information was categorized as true, false, misleading, or exaggerated. RESULTS: We identified 637 COVID-19 vaccine-related items: 91% were rumors and 9% were conspiracy theories from 52 countries. Of the 578 rumors, 36% were related to vaccine development, availability, and access, 20% related to morbidity and mortality, 8% to safety, efficacy, and acceptance, and the rest were other categories. Of the 637 items, 5% (30/) were true, 83% (528/637) were false, 10% (66/637) were misleading, and 2% (13/637) were exaggerated. CONCLUSIONS: Rumors and conspiracy theories may lead to mistrust contributing to vaccine hesitancy. Tracking COVID-19 vaccine misinformation in real-time and engaging with social media to disseminate correct information could help safeguard the public against misinformation.
Subject(s)
COVID-19/psychology , Information Dissemination/methods , Vaccination Refusal/psychology , COVID-19 Vaccines/pharmacology , Communication , Cross-Sectional Studies , Humans , Information Dissemination/ethics , Public Health , SARS-CoV-2/pathogenicity , Social Media , Surveys and Questionnaires , Vaccination/methodsABSTRACT
Infodemics, often including rumors, stigma, and conspiracy theories, have been common during the COVID-19 pandemic. Monitoring social media data has been identified as the best method for tracking rumors in real time and as a possible way to dispel misinformation and reduce stigma. However, the detection, assessment, and response to rumors, stigma, and conspiracy theories in real time are a challenge. Therefore, we followed and examined COVID-19-related rumors, stigma, and conspiracy theories circulating on online platforms, including fact-checking agency websites, Facebook, Twitter, and online newspapers, and their impacts on public health. Information was extracted between December 31, 2019 and April 5, 2020, and descriptively analyzed. We performed a content analysis of the news articles to compare and contrast data collected from other sources. We identified 2,311 reports of rumors, stigma, and conspiracy theories in 25 languages from 87 countries. Claims were related to illness, transmission and mortality (24%), control measures (21%), treatment and cure (19%), cause of disease including the origin (15%), violence (1%), and miscellaneous (20%). Of the 2,276 reports for which text ratings were available, 1,856 claims were false (82%). Misinformation fueled by rumors, stigma, and conspiracy theories can have potentially serious implications on the individual and community if prioritized over evidence-based guidelines. Health agencies must track misinformation associated with the COVID-19 in real time, and engage local communities and government stakeholders to debunk misinformation.
