8R12 | pdb_00008r12

Structure of compound 8 bound to SARS-CoV-2 main protease


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free: 
    0.238 (Depositor), 0.230 (DCC) 
  • R-Value Work: 
    0.209 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 
    0.211 (Depositor) 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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This is version 1.1 of the entry. See complete history


Literature

Identification of SARS-CoV-2 Mpro inhibitors through deep reinforcement learning for de novo drug design and computational chemistry approaches.

Hazemann, J.Kimmerlin, T.Lange, R.Sweeney, A.M.Bourquin, G.Ritz, D.Czodrowski, P.

(2024) RSC Med Chem 15: 2146-2159

  • DOI: https://doi.org/10.1039/d4md00106k
  • Primary Citation of Related Structures:  
    8R11, 8R12, 8R14, 8R16

  • PubMed Abstract: 

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease (COVID-19) since its emergence in December 2019. As of January 2024, there has been over 774 million reported cases and 7 million deaths worldwide. While vaccination efforts have been successful in reducing the severity of the disease and decreasing the transmission rate, the development of effective therapeutics against SARS-CoV-2 remains a critical need. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme required for viral replication and has been identified as a promising target for drug development. In this study, we report the identification of novel Mpro inhibitors, using a combination of deep reinforcement learning for de novo drug design with 3D pharmacophore/shape-based alignment and privileged fragment match count scoring components followed by hit expansions and molecular docking approaches. Our experimentally validated results show that 3 novel series exhibit potent inhibitory activity against SARS-CoV-2 Mpro, with IC 50 values ranging from 1.3 μM to 2.3 μM and a high degree of selectivity. These findings represent promising starting points for the development of new antiviral therapies against COVID-19.


  • Organizational Affiliation

    Physical Chemistry, Chemistry Department, Johannes Gutenberg University Duesbergweg 10-14 55128 Mainz Germany czodpaul@uni-mainz.de.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3C-like proteinase
A, B
306Severe acute respiratory syndrome coronavirus 2Mutation(s): 0 
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 Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0DTD1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
XH9 (Subject of Investigation/LOI)
Query on XH9

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
2-[[4-(5-chloranylpyridin-3-yl)carbonyl-1,4-diazepan-1-yl]methyl]benzenecarbonitrile
C19 H19 Cl N4 O
VIHXPVLCTFBBEL-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
F [auth B]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
G [auth B]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.59 Å
  • R-Value Free:  0.238 (Depositor), 0.230 (DCC) 
  • R-Value Work:  0.209 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 0.211 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.01α = 90
b = 100.34β = 90
c = 104.55γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted XH9Click on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-02-07
    Type: Initial release
  • Version 1.1: 2024-07-03
    Changes: Database references