2GZ8

Structure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of SARS-CoV Main Protease

2GZ8 の概要

• エントリーDOI: 10.2210/pdb2gz8/pdb
• 関連するPDBエントリー: 2GZ7 2GZ9
• 分子名称: Replicase polyprotein 1ab, S-[5-(TRIFLUOROMETHYL)-4H-1,2,4-TRIAZOL-3-YL] 5-(PHENYLETHYNYL)FURAN-2-CARBOTHIOATE (3 entities in total)
• 機能のキーワード: sars cov main protease, hydrolase
• 由来する生物種: SARS coronavirus
• 細胞内の位置: 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). Helicase: Host endoplasmic reticulum-Golgi intermediate compartment (Potential). Uridylate-specific endoribonuclease: Host cytoplasm, host perinuclear region (By similarity): P59641
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34239.95

構造登録者

Lu, I.L.,Wu, S.Y. (登録日: 2006-05-11, 公開日: 2006-08-29, 最終更新日: 2023-10-25)

主引用文献

Lu, I.L.,Mahindroo, N.,Liang, P.H.,Peng, Y.H.,Kuo, C.J.,Tsai, K.C.,Hsieh, H.P.,Chao, Y.S.,Wu, S.Y.
Structure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Main Protease
J.Med.Chem., 49:5154-5161, 2006

PubMed Abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58,855 compounds followed by the testing of potential compounds for SARS-CoV M(pro) inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search. Twenty-one analogues derived from these two hits exhibited IC50 values below 50 microM, with the most potent one showing 0.3 microM. Furthermore, the complex structures of two potent inhibitors with SARS-CoV M(pro) were solved by X-ray crystallography. They bind to the protein in a distinct manner compared to all published SARS-CoV M(pro) complex structures. They inhibit SARS-CoV M(pro) activity via intensive H-bond network and hydrophobic interactions, without the formation of a covalent bond. Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms, particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.

PubMed: 16913704
DOI: 10.1021/jm060207o

実験手法

X-RAY DIFFRACTION (1.97 Å)