3MJ5

Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation

Summary for 3MJ5

• Entry DOI: 10.2210/pdb3mj5/pdb
• Related: 2FE8 3E9S
• Descriptor: Replicase polyprotein 1a, N-(1,3-benzodioxol-5-ylmethyl)-1-[(1R)-1-naphthalen-1-ylethyl]piperidine-4-carboxamide, ZINC ION, ... (4 entities in total)
• Functional Keywords: non-covalent inhibitor, cysteine protease, sars coronavirus, zinc-finger, viral protein
• Biological source: SARS coronavirus (SARS-CoV)
• Cellular location: Non-structural protein 3: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 4: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 6: Host membrane; Multi-pass membrane protein (Potential). Non-structural protein 7: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 8: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 9: Host cytoplasm, host perinuclear region (By similarity). Non-structural protein 10: Host cytoplasm, host perinuclear region (By similarity): P0C6U8
• Total number of polymer chains: 2
• Total formula weight: 72004.39

Authors

Mesecar, A.D.,Ratia, K.M.,Pegan, S.D. (deposition date: 2010-04-12, release date: 2010-06-30, Last modification date: 2024-11-20)

Primary citation

Ghosh, A.K.,Takayama, J.,Rao, K.V.,Ratia, K.,Chaudhuri, R.,Mulhearn, D.C.,Lee, H.,Nichols, D.B.,Baliji, S.,Baker, S.C.,Johnson, M.E.,Mesecar, A.D.
Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation
J.Med.Chem., 53:4968-4979, 2010

PubMed Abstract: The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15 h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15 g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.

PubMed: 20527968
DOI: 10.1021/jm1004489

Experimental method

X-RAY DIFFRACTION (2.63 Å)