About: Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches

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About: Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches
Creator	Abagyan, Ruben Ae, Dai Ae, Jordan Ae, Totrov Byrd Ae, M Chelsea, A Dongcheng, A Hruby, Dennis Katritch, Vsevolod Maxim, A Raush, Eugene Robert, A Tseitin, Vladimir
Source	Medline; PMC
abstract	Essential for viral replication and highly conserved among poxviridae, the vaccinia virus I7L ubiquitin-like proteinase (ULP) is an attractive target for development of smallpox antiviral drugs. At the same time, the I7L proteinase exemplifies several interesting challenges from the rational drug design perspective. In the absence of a published I7L X-ray structure, we have built a detailed 3D model of the I7L ligand binding site (S2–S2′ pocket) based on exceptionally high structural conservation of this site in proteases of the ULP family. The accuracy and limitations of this model were assessed through comparative analysis of available X-ray structures of ULPs, as well as energy based conformational modeling. The 3D model of the I7L ligand binding site was used to perform covalent docking and VLS of a comprehensive library of about 230,000 available ketone and aldehyde compounds. Out of 456 predicted ligands, 97 inhibitors of I7L proteinase activity were confirmed in biochemical assays (∼20% overall hit rate). These experimental results both validate our I7L ligand binding model and provide initial leads for rational optimization of poxvirus I7L proteinase inhibitors. Thus, fragments predicted to bind in the prime portion of the active site can be combined with fragments on non-prime side to yield compounds with improved activity and specificity.
has issue date	2007-10-25(xsd:dateTime)
bibo:doi	10.1007/s10822-007-9138-7
bibo:pmid	17960327
has license	no-cc
sha1sum (hex)	4e6dc4220330dc4299ea6cb20dead9670fc24897
schema:url	https://doi.org/10.1007/s10822-007-9138-7
resource representing a document's title	Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches
has PubMed Central identifier	PMC7087885
has PubMed identifier	17960327
schema:publication	J Comput Aided Mol Des
resource representing a document's body	covid:4e6dc4220330dc4299ea6cb20dead9670fc24897#body_text
is schema:about of	named entity 'predicted' named entity 'initial' named entity 'attractive' named entity 'ligands' named entity 'proteinase' named entity 'ubiquitin-like' named entity 'rational drug design' named entity 'comprehensive' named entity 'ketone' named entity 'development' named entity 'docking' named entity 'binding site' named entity 'improved' named entity 'ligand' named entity 'compounds' named entity 'proteinase' named entity 'proteinase' named entity 'highly conserved' named entity 'ligand binding' named entity 'antiviral drugs' named entity 'ligand binding site' named entity 'X-ray structure' named entity 'poxviridae' named entity 'rational drug design' named entity 'covalent' named entity 'proteinase' named entity 'SAR' named entity 'binding pocket' named entity 'substrate binding' named entity 'peptide' named entity 'acyl' named entity 'West Nile' named entity 'substrate' named entity 'proteolytic activity' named entity 'Biochemical studies' named entity 'aliphatic' named entity 'ligand binding' named entity 'binding site' named entity 'acyl' named entity 'active site' named entity 'ligands' named entity 'active site' named entity 'antivirals' named entity 'covalent' named entity 'electrostatic' named entity 'orthologues' named entity 'thio' named entity 'motif' named entity 'amino acid side chain' named entity 'aromatic' named entity 'vaccinia' named entity 'active site' named entity 'substrate' named entity 'steric clash' named entity 'methyl group' named entity 'ketone' named entity 'ICM' named entity 'protein' named entity 'clinical development' named entity 'proteinase' named entity 'active site' named entity 'substrate' named entity 'conformations' named entity 'substrate' named entity 'structural model' named entity 'ligand' named entity 'cleavage site' named entity '3.5' named entity 'enzyme'

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