Structure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Main Protease

Lu, I-Lin; Mahindroo, Neeraj; Liang, Po‐Huang; Peng, Yi-Hui; Kuo, C.J.; Tsai, Keng‐Chang; Hsieh, Hsing‐Pang; Chao, Yu‐Sheng; Wu, Su-Ying

doi:10.1021/jm060207o

Cited by 141 publications

(125 citation statements)

References 37 publications

(68 reference statements)

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“…Lu et al picked a very attractive target for their docking campaign: they tried to find novel binders of the SARS coronavirus main protease [35]. Using the program GOLD, they screened a library of 58,855 compounds, which yielded two hits binding at approximately 10 µM.…”

Section: Less Than Complete Studiesmentioning

confidence: 99%

Docking Screens: Right for the Right Reasons?

Kolb¹,

Irwin²

2009

CTMC

114

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Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so the score it receives is biophysically sound. If the correct binding pose is not predicted, a skeptic might well infer that the discovery was serendipitous. Surveying over 15 years of the docking literature, we were surprised to discover how rarely sufficient evidence is presented to establish whether docking actually worked for the right reasons. The paucity of experimental tests of theoretically predicted poses undermines confidence in a technique that has otherwise become widely accepted. Of course, solving a crystal structure is not always possible, and even when it is, it can be a lot of work, and is not readily accessible to all groups. Even when a structure can be determined, investigators may prefer to gloss over an erroneous structural prediction to better focus on their discovery. Still, the absence of a direct test of theory by experiment is a loss for method developers seeking to understand and improve docking methods. We hope this review will motivate investigators to solve structures and compare them with their predictions whenever possible, to advance the field.

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Section: Less Than Complete Studiesmentioning

confidence: 99%

Docking Screens: Right for the Right Reasons?

Kolb¹,

Irwin²

2009

CTMC

114

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“…SARS-CoV and MERS-CoV belong to the genus Betacoronavirus but pertain to highly distinct phylogenetic clades termed b and c, respectively (de Groot et al, 2013). In case of SARS-CoV, the bestcharacterized potential antiviral drug targets are the two viral proteases, the main protease (M pro , also called 3C-like protease, 3CL pro ) (Hilgenfeld and Peiris, 2013;Anand et al, 2003;Yang et al, 2003Yang et al, , 2005Xu et al, 2005;Lu et al, 2006;Verschueren et al, 2008;Zhu et al, 2011;Kilianski et al, 2013) and the papain-like protease (PL pro ) (Hilgenfeld and Peiris, 2013;Kilianski et al, 2013;Barretto et al, 2005;Ratia et al, 2006Ratia et al, , 2008Baez-Santos et al, 2014). The latter enzyme exists in all coronaviruses (Woo et al, 2010) and has been shown to be responsible for releasing non-structural proteins (Nsp) 1, 2, and 3 from the N-terminal part of polyproteins 1a and 1ab.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

et al. 2014

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The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL(pro)) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL(pro) is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL(pro), compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL(pro). The unique features observed in the crystal structure of the MERS-CoV PL(pro) should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.

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“…A few non-covalent, competitive inhibitors 10 and peptidic, covalent inhibitors have been visualized in SARS 3CL pro crystal structures. 7,8,[11][12][13] The covalent inhibitors studied to date carry either a halomethyl ketone, an epoxide or a 1,4 Michael acceptor function as the reactive "warheads".…”

Section: Introductionmentioning

confidence: 99%

A Mechanistic View of Enzyme Inhibition and Peptide Hydrolysis in the Active Site of the SARS-CoV 3C-like Peptidase

Jiang

Niu

Cherney

et al. 2007

Journal of Molecular Biology

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The 3C-like main peptidase 3CL pro is a viral polyprotein processing enzyme essential for the viability of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). While it is generalized that 3CL pro and the structurally related 3C pro viral peptidases cleave their substrates via a mechanism similar to that underlying the peptide hydrolysis by chymotrypsin-like serine proteinases (CLSPs), some of the hypothesized key intermediates have not been structurally characterized. Here, we present three crystal structures of SARS 3CL pro in complex with each of two members of a new class of peptide-based phthalhydrazide inhibitors. Both inhibitors form an unusual thiiranium ring with the nucleophilic sulfur atom of Cys145, trapping the enzyme's catalytic residues in configurations similar to the intermediate states proposed to exist during the hydrolysis of native substrates. Most significantly, our crystallographic data are consistent with a scenario in which a water molecule, possibly via indirect coordination from the carbonyl oxygen of Thr26, has initiated nucleophilic attack on the enzyme-bound inhibitor. Our data suggest that this structure resembles that of the proposed tetrahedral intermediate during the deacylation step of normal peptidyl cleavage.

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Structure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Main Protease

Cited by 141 publications

References 37 publications

Docking Screens: Right for the Right Reasons?

Docking Screens: Right for the Right Reasons?

Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features

A Mechanistic View of Enzyme Inhibition and Peptide Hydrolysis in the Active Site of the SARS-CoV 3C-like Peptidase

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