Aurélien F. A. Moumbock

Abstract

Membrane proteins represent about 30% of all proteins encoded by the human genome, of which G-protein coupled receptors (GPCRs) are the largest superfamily. Of particular interest is CC chemokine receptor type 9 (CCR9), a drug target in inflammatory bowel disease. Vercirnon is a highly potent intracellular allosteric antagonist of CCR9 that unfortunately failed in clinical trials due to poor efficacy. Starting from a resolved co-crystal structure of the CCR9-vercirnon complex, we modeled several vercirnon congeners in the CCR9 binding pocket and thereby generated a reliable energy-optimized pharmacophore to guide the discovery, design, and synthesis of novel CCR9 allosteric antagonists.

Transmembrane proteases are another important class of drug targets. The causative pathogen of the coronavirus disease 2019 (COVID-19) — namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — is primed by the transmembrane protease serine 2 (TMPRSS2) prior to its fusion to the angiotensin converting enzyme 2 (ACE2) of vertebrates. It has been demonstrated that highly potent extracellular TMPRSS2 covalent inhibitors such as camostat and nafamostat can impede SARS-CoV-2 host cell entry. However, the two aforementioned inhibitors are metabolically unstable in vivo. In the search for metabolically stable TMPRSS2 covalent inhibitors, we adopted a drug repurposing approach using a resolved structure of the TMPRSS2-nafamostat complex and the covalent ligands of CovPDB (http://www.pharmbioinf.uni-freiburg.de/covpdb/), a database we recently developed.

Methods

• Pharmacophore Modeling
• Molecular Docking
• Metadynamics
• Organic Synthesis
• Biochemical, Biophysical, and Cell-Based Assays

Publications

https://freidok.uni-freiburg.de/pers/265541