RESUMO
This research is carried out to explore the hypoglycemic activity of Syzygium cumini seed extracts by in vitro, in vivo, and in silico methods. For in vitro studies the α-amylase and α-glucosidase enzyme inhibition assays were employed. For in vivo studies 30 alloxan induced Wistar rats were used. They were orally administered with glibenclamide and low/high dose of the extracts and were monitored regularly for the change in blood glucose levels for about 28 days. The in silico molecular docking was conducted to evaluate the binding interaction of 1,2,3-Benzenetriol with human pancreatic α-amylase and α-glucosidase. It was found that all the extracts were able to inhibit the α-amylase and α-glucosidase enzymes. Among which the acetone extract showed greater inhibition with 72.52 ± 0.51% and 63.02 ± 0.73% for both the enzymes, respectively. There was significant (p < 0.05) reduction in blood glucose levels in the rats administered with glibenclamide and extracts. In silico docking results revealed that the compound 1,2,3-Benzenetriol exhibited the highest binding affinity for human pancreatic α-amylase with binding energy -7.7 kcal/mol. Thus suggesting the utilization of S. cumini seeds in the management of diabetes mellitus.Communicated by Ramaswamy H. Sarma.
RESUMO
The COVID-19 pandemic is a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Future pandemics could be prevented by accessible, easily deployable broad-spectrum oral antivirals and open knowledge bases that derisk and accelerate novel antiviral discovery and development. Here, we report the results of the COVID Moonshot, a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical scaffold that is differentiated from current clinical candidates in terms of toxicity, resistance, and pharmacokinetics liabilities, and developed it into noncovalent orally-bioavailable nanomolar inhibitors with clinical potential. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations. In the process, we generated a detailed map of the structural plasticity of the main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>500 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.
RESUMO
We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.