9Z0C | pdb_00009z0c

SARS-CoV-2 Papain-like Protease (PLpro) in complex with Fragment 7

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 
    0.252 (Depositor), 0.252 (DCC) 
  • R-Value Work: 
    0.208 (Depositor), 0.208 (DCC) 
  • R-Value Observed: 
    0.210 (Depositor) 

Starting Model: experimental
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Literature

Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease.

Wei, Q., Taylor, A.J., Miriyala, N., Barmade, M.A., Gentry, Z.O., Anderson-Daniels, J., Teuscher, K.B., Crow, M.M., Apakama, C., South, T.M., Rietz, T.A., Amporndanai, K., Phan, J., Sensintaffar, J.L., Denison, M., Lee, T., Fesik, S.W.

(2026) J Med Chem 

  • DOI: https://doi.org/10.1021/acs.jmedchem.5c03704
  • Primary Citation of Related Structures:  
    9Z0C, 9Z0D

  • PubMed Abstract: 

    The papain-like protease (PL Pro ) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PL Pro led to the identification of a novel class of spiro[chromane-2,4'-piperidin]-4-one inhibitors exemplified by lead compound 7 . High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PL Pro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC 50 = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC 50 = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.

    • Organizational Affiliation: 
    • Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States.

Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Papain-like protease nsp3326Severe acute respiratory syndrome coronavirus 2Mutation(s): 1 
Gene Names: rep, 1a-1b
EC: 3.4.19.12 (PDB Primary Data), 3.4.22 (PDB Primary Data)
UniProt
Find proteins for P0DTD1 (Severe acute respiratory syndrome coronavirus 2)
Explore P0DTD1 
Go to UniProtKB:  P0DTD1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0DTD1
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free:  0.252 (Depositor), 0.252 (DCC) 
  • R-Value Work:  0.208 (Depositor), 0.208 (DCC) 
  • R-Value Observed: 0.210 (Depositor) 
Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.784α = 90
b = 77.784β = 90
c = 231.185γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data

  • Released Date: 2026-02-18 
    • Deposition Author(s): Taylor, A.J.
Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesU19AI171292

Revision History  (Full details and data files)

  • Version 1.0: 2026-02-18
    Type: Initial release