TY  - JOUR
AU  - Gossen, Jonas
AU  - Albani, Simone
AU  - Hanke, Anton
AU  - Joseph, Benjamin P.
AU  - Bergh, Cathrine
AU  - Kuzikov, Maria
AU  - Costanzi, Elisa
AU  - Manelfi, Candida
AU  - Storici, Paola
AU  - Gribbon, Philip
AU  - Beccari, Andrea R.
AU  - Talarico, Carmine
AU  - Spyrakis, Francesca
AU  - Lindahl, Erik
AU  - Zaliani, Andrea
AU  - Carloni, Paolo
AU  - Wade, Rebecca C.
AU  - Musiani, Francesco
AU  - Kokh, Daria B.
AU  - Rossetti, Giulia
TI  - A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics
JO  - ACS pharmacology & translational science
VL  - 4
IS  - 3
SN  - 2575-9108
CY  - Washington, DC
PB  - ACS Publications
M1  - FZJ-2021-01324
SP  - 1079–1095
PY  - 2021
AB  - The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of ∼30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing ∼200 virtual screenings of compound libraries on selected protein structures, we redefine the protein’s druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.
LB  - PUB:(DE-HGF)16
C6  - pmid:34136757
UR  - <Go to ISI:>//WOS:000662229400006
DO  - DOI:10.1021/acsptsci.0c00215
UR  - https://juser.fz-juelich.de/record/891037
ER  -