Published in Henry Rzepa's Blog

Earlier this year, Molnupiravir hit the headlines as a promising antiviral drug. This is now followed by Paxlovid, which is the first small molecule to be aimed by design at the SAR-CoV-2 protein and which is reported as reducing greatly the risk of hospitalization or death when given within three days of symptoms appearing in high risk patients. The Wikipedia page (first created in 2021) will display a pretty good JSmol 3D model of this;

References

Colloid and Surface ChemistryBiochemistryGeneral ChemistryCatalysis

Discovery of a Potent and Selective Covalent Inhibitor and Activity-Based Probe for the Deubiquitylating Enzyme UCHL1, with Antifibrotic Activity

Published in Journal of the American Chemical Society
Authors Nattawadee Panyain, Aurélien Godinat, Thomas Lanyon-Hogg, Sofía Lachiondo-Ortega, Edward J. Will, Christelle Soudy, Milon Mondal, Katie Mason, Sarah Elkhalifa, Lisa M. Smith, Jeanine A. Harrigan, Edward W. Tate
Organic ChemistryDrug DiscoveryPharmaceutical SciencePharmacologyMolecular Medicine

Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe

We report the characterization of a UCHL1 covalent inhibitor based on a thiazole cyanopyrrolidine scaffold and a closely-related activity-based probe (ABP) which was used to generate a quantitative profile for on- and off-targets in human cells.

Genetics

CovalentInDB: a comprehensive database facilitating the discovery of covalent inhibitors

Published in Nucleic Acids Research
Authors Hongyan Du, Junbo Gao, Gaoqi Weng, Junjie Ding, Xin Chai, Jinping Pang, Yu Kang, Dan Li, Dongsheng Cao, Tingjun Hou

AbstractInhibitors that form covalent bonds with their targets have traditionally been considered highly adventurous due to their potential off-target effects and toxicity concerns. However, with the clinical validation and approval of many covalent inhibitors during the past decade, design and discovery of novel covalent inhibitors have attracted increasing attention. A large amount of scattered experimental data for covalent inhibitors have been reported, but a resource by integrating the experimental information for covalent inhibitor discovery is still lacking. In this study, we presented Covalent Inhibitor Database (CovalentInDB), the largest online database that provides the structural information and experimental data for covalent inhibitors. CovalentInDB contains 4511 covalent inhibitors (including 68 approved drugs) with 57 different reactive warheads for 280 protein targets. The crystal structures of some of the proteins bound with a covalent inhibitor are provided to visualize the protein–ligand interactions around the binding site. Each covalent inhibitor is annotated with the structure, warhead, experimental bioactivity, physicochemical properties, etc. Moreover, CovalentInDB provides the covalent reaction mechanism and the corresponding experimental verification methods for each inhibitor towards its target. High-quality datasets are downloadable for users to evaluate and develop computational methods for covalent drug design. CovalentInDB is freely accessible at http://cadd.zju.edu.cn/cidb/.