3V3M

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease in Complex with N-[(1R)-2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-N-(4-tert-butylphenyl)furan-2-carboxamide inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery, Synthesis, And Structure-Based Optimization of a Series of N-(tert-Butyl)-2-(N-arylamido)-2-(pyridin-3-yl) Acetamides (ML188) as Potent Noncovalent Small Molecule Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) 3CL Protease.

Jacobs, J.Grum-Tokars, V.Zhou, Y.Turlington, M.Saldanha, S.A.Chase, P.Eggler, A.Dawson, E.S.Baez-Santos, Y.M.Tomar, S.Mielech, A.M.Baker, S.C.Lindsley, C.W.Hodder, P.Mesecar, A.Stauffer, S.R.

(2013) J Med Chem 56: 534-546

  • DOI: https://doi.org/10.1021/jm301580n
  • Primary Citation of Related Structures:  
    3V3M

  • PubMed Abstract: 

    A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.


  • Organizational Affiliation

    Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3C-like proteinase306Severe acute respiratory syndrome-related coronavirusMutation(s): 0 
Gene Names: 1a
EC: 3.4.19.12 (PDB Primary Data), 3.4.22.69 (PDB Primary Data), 3.4.22 (PDB Primary Data)
UniProt
Find proteins for P0C6U8 (Severe acute respiratory syndrome coronavirus)
Explore P0C6U8 
Go to UniProtKB:  P0C6U8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0C6U8
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0EN
Query on 0EN

Download Ideal Coordinates CCD File 
B [auth A]N-[(1R)-2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-N-(4-tert-butylphenyl)furan-2-carboxamide
C26 H31 N3 O3
JXGIYKRRPGCLFV-JOCHJYFZSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0EN PDBBind:  3V3M IC50: 4800 (nM) from 1 assay(s)
BindingDB:  3V3M IC50: min: 1500, max: 4890 (nM) from 3 assay(s)
EC50: 1.29e+4 (nM) from 1 assay(s)
Binding MOAD:  3V3M IC50: 4800 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 106.733α = 90
b = 82.668β = 106.03
c = 53.117γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
AMoREphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-01-16
    Type: Initial release
  • Version 1.1: 2013-02-13
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations