8WTI | pdb_00008wti

Crystal structure of the SARS-CoV-2 main protease in complex with 20j

PDB DOI: https://doi.org/10.2210/pdb8WTI/pdb

Classification: VIRAL PROTEIN
Organism(s): Severe acute respiratory syndrome coronavirus 2
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2023-10-18 Released: 2024-08-28
Deposition Author(s): Zeng, R., Zhao, X., Yang, S.Y., Lei, J.
Funding Organization(s): National Natural Science Foundation of China (NSFC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.50 Å
R-Value Free:
0.201 (Depositor), 0.200 (DCC)
R-Value Work:
0.172 (Depositor), 0.170 (DCC)
R-Value Observed:
0.173 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Discovery of alpha-Ketoamide inhibitors of SARS-CoV-2 main protease derived from quaternized P1 groups.

Huang, Q., Quan, B., Chen, Y., Zhao, X., Zhou, Y., Huang, C., Qiao, J., Wang, Y., Li, Y., Yang, S., Lei, J., Li, L.

(2024) Bioorg Chem 143: 107001-107001

PubMed: 38101266 Search on PubMed
DOI: https://doi.org/10.1016/j.bioorg.2023.107001
Primary Citation of Related Structures:
8WTI

PubMed Abstract:
Although the SARS-CoV-2 pandemic has ended, multiple sporadic cases still exist, posing a request for more antivirals. The main protease (M ^pro) of SARS-CoV-2, a key enzyme for viral replication, is an attractive target for drug development. Here, we report the discovery of a new potent α-ketoamide-containing M ^pro inhibitor, N-((R)-1-cyclohexyl-2-(((R)-3-methoxy-1-oxo-1-((1-(2-oxo-2-((thiazol-2-ylmethyl)amino)acetyl)cyclobutyl)amino)propan-2-yl)amino)-2-oxoethyl)-4,4-difluorocyclohexane-1-carboxamide (20j). This compound presented promising enzymatic inhibitory activity against SARS-CoV-2 M ^pro with an IC ₅₀ value of 19.0 nM, and an excellent antiviral activity in cell-based assay with an EC ₅₀ value of 138.1 nM. This novel covalent inhibitor may be used as a lead compound for subsequent drug discovery against SARS-CoV-2.

Organizational Affiliation

Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.

Macromolecule Content

Total Structure Weight: 69.3 kDa
Atom Count: 5,697
Modeled Residue Count: 609
Deposited Residue Count: 612
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
3C-like proteinase nsp5	A, B	306	Severe acute respiratory syndrome coronavirus 2	Mutation(s): 1 EC: 3.4.22.69
UniProt
Find proteins for P0DTD1 (Severe acute respiratory syndrome coronavirus 2) Explore P0DTD1 Go to UniProtKB: P0DTD1
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P0DTD1
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
X1Z (Subject of Investigation/LOI) Query on X1Z Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain G [auth B] MOL2 format, chain C [auth A] MOL2 format, chain G [auth B] mmCIF format, chain C [auth A] mmCIF format, chain G [auth B]	C [auth A], G [auth B]	~{N}-[(1~{R})-1-cyclohexyl-2-[[(2~{R})-3-methoxy-1-oxidanylidene-1-[[1-[(1~{S})-1-oxidanyl-2-oxidanylidene-2-(1,3-thiazol-2-ylmethylamino)ethyl]cyclobutyl]amino]propan-2-yl]amino]-2-oxidanylidene-ethyl]-4,4-bis(fluoranyl)cyclohexane-1-carboxamide C₂₉ H₄₃ F₂ N₅ O₆ S UHHQICGXTSMHIU-YMPZKCBVSA-N		Interactions Focus chain C [auth A] Focus chain G [auth B] Interactions & Density Focus chain C [auth A] Focus chain G [auth B]
PEG Query on PEG Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A]	D [auth A], E [auth A]	DI(HYDROXYETHYL)ETHER C₄ H₁₀ O₃ MTHSVFCYNBDYFN-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Interactions & Density Focus chain D [auth A] Focus chain E [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]