7L12

CRYSTAL STRUCTURE OF THE SARS-COV-2(2019-NCOV) MAIN PROTEASE IN COMPLEX WITH COMPOUND 14

Summary for 7L12

• Entry DOI: 10.2210/pdb7l12/pdb
• Descriptor: 3C-like proteinase, (5S)-5-{3-[3-(benzyloxy)-5-chlorophenyl]-2-oxo[2H-[1,3'-bipyridine]]-5-yl}pyrimidine-2,4(3H,5H)-dione (3 entities in total)
• Functional Keywords: novel coronavirus, antiviral, drug design, viral protein, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 1
• Total formula weight: 34324.46

Authors

Deshmukh, M.G.,Ippolito, J.A.,Zhang, C.H.,Jorgensen, W.L.,Anderson, K.S. (deposition date: 2020-12-14, release date: 2021-03-03, Last modification date: 2023-10-18)

Primary citation

Zhang, C.H.,Stone, E.A.,Deshmukh, M.,Ippolito, J.A.,Ghahremanpour, M.M.,Tirado-Rives, J.,Spasov, K.A.,Zhang, S.,Takeo, Y.,Kudalkar, S.N.,Liang, Z.,Isaacs, F.,Lindenbach, B.,Miller, S.J.,Anderson, K.S.,Jorgensen, W.L.
Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations.
Acs Cent.Sci., 7:467-475, 2021

PubMed Abstract: Starting from our previous finding of 14 known drugs as inhibitors of the main protease (M) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC values in a kinetic assay. Free-energy perturbation (FEP) calculations for M-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to M. Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.

PubMed: 33786375
DOI: 10.1021/acscentsci.1c00039

Experimental method

X-RAY DIFFRACTION (1.8 Å)