8PH4

Co-Crystal structure of the SARS-CoV2 main protease Nsp5 with an Uracil-carrying X77-like inhibitor

Summary for 8PH4

• Entry DOI: 10.2210/pdb8ph4/pdb
• Descriptor: 3C-like proteinase nsp5, MALONATE ION, ~{N}-(4-~{tert}-butylphenyl)-~{N}-[(1~{S})-2-(cyclohexylamino)-2-oxidanylidene-1-pyridin-3-yl-ethyl]-2,6-bis(oxidanylidene)-5~{H}-pyrimidine-5-carboxamide, ... (6 entities in total)
• Functional Keywords: mpro, inhibitor, complex, protease, antiviral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 69891.63

Authors

Barthel, T.,Altincekic, N.,Jores, N.,Wollenhaupt, J.,Weiss, M.S.,Schwalbe, H. (deposition date: 2023-06-18, release date: 2024-01-31, Last modification date: 2024-02-28)

Primary citation

Altincekic, N.,Jores, N.,Lohr, F.,Richter, C.,Ehrhardt, C.,Blommers, M.J.J.,Berg, H.,Ozturk, S.,Gande, S.L.,Linhard, V.,Orts, J.,Abi Saad, M.J.,Butikofer, M.,Kaderli, J.,Karlsson, B.G.,Brath, U.,Hedenstrom, M.,Grobner, G.,Sauer, U.H.,Perrakis, A.,Langer, J.,Banci, L.,Cantini, F.,Fragai, M.,Grifagni, D.,Barthel, T.,Wollenhaupt, J.,Weiss, M.S.,Robertson, A.,Bax, A.,Sreeramulu, S.,Schwalbe, H.
Targeting the Main Protease (M pro , nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies.
Acs Chem.Biol., 19:563-574, 2024

PubMed Abstract: The main protease M, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with M. These investigations resulted in the four-armed compound that binds directly to M. could be cocrystallized with M revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.

PubMed: 38232960
DOI: 10.1021/acschembio.3c00720

Experimental method

X-RAY DIFFRACTION (1.69 Å)