7NW2

Crystal Structure of SARS-CoV-2 main protease in complex with LON-WEI-adc59df6-47

Summary for 7NW2

• Entry DOI: 10.2210/pdb7nw2/pdb
• Descriptor: 3C-like proteinase, ~{N}-(4-~{tert}-butylphenyl)-~{N}-[(1~{R})-2-[2-(3-fluorophenyl)ethylamino]-2-oxidanylidene-1-pyridin-3-yl-ethyl]propanamide, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: diamond i04-1, fragment screening, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 68851.31

Authors

Fearon, D.,Douangamath, A.,Aimon, A.,Brandao-Neto, J.,Dias, A.,Dunnett, L.,Gehrtz, P.,Gorrie-Stone, T.J.,Lukacik, P.,Powell, A.J.,Skyner, R.,Strain-Damerell, C.M.,Zaidman, D.,London, N.,Walsh, M.A.,von Delft, F.,Covid Moonshot Consortium (deposition date: 2021-03-16, release date: 2021-07-07, Last modification date: 2024-11-13)

Primary citation

Zaidman, D.,Gehrtz, P.,Filep, M.,Fearon, D.,Gabizon, R.,Douangamath, A.,Prilusky, J.,Duberstein, S.,Cohen, G.,Owen, C.D.,Resnick, E.,Strain-Damerell, C.,Lukacik, P.,Barr, H.,Walsh, M.A.,von Delft, F.,London, N.
An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 M pro inhibitor.
Cell Chem Biol, 28:1795-1806.e5, 2021

PubMed Abstract: Designing covalent inhibitors is increasingly important, although it remains challenging. Here, we present covalentizer, a computational pipeline for identifying irreversible inhibitors based on structures of targets with non-covalent binders. Through covalent docking of tailored focused libraries, we identify candidates that can bind covalently to a nearby cysteine while preserving the interactions of the original molecule. We found ∼11,000 cysteines proximal to a ligand across 8,386 complexes in the PDB. Of these, the protocol identified 1,553 structures with covalent predictions. In a prospective evaluation, five out of nine predicted covalent kinase inhibitors showed half-maximal inhibitory concentration (IC) values between 155 nM and 4.5 μM. Application against an existing SARS-CoV M reversible inhibitor led to an acrylamide inhibitor series with low micromolar IC values against SARS-CoV-2 M. The docking was validated by 12 co-crystal structures. Together these examples hint at the vast number of covalent inhibitors accessible through our protocol.

PubMed: 34174194
DOI: 10.1016/j.chembiol.2021.05.018

Experimental method

X-RAY DIFFRACTION (2.1 Å)