7L11
CRYSTAL STRUCTURE OF THE SARS-COV-2(2019-NCOV) MAIN PROTEASE IN COMPLEX WITH COMPOUND 5
Summary for 7L11
Entry DOI | 10.2210/pdb7l11/pdb |
Descriptor | 3C-like proteinase, 2-[3-(3-chloro-5-propoxyphenyl)-2-oxo[2H-[1,3'-bipyridine]]-5-yl]benzonitrile (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 | 2 |
Total formula weight | 68534.91 |
Authors | Deshmukh, M.G.,Ippolito, J.A.,Stone, E.A.,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 Cited by 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: 33786375DOI: 10.1021/acscentsci.1c00039 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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