Linked Life Data

19437467

Source:http://linkedlifedata.com/resource/pubmed/id/19437467

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2009-7-6
pubmed:abstractText
Novel and potent inhibitors of Plasmodium falciparum plasmepsin II were identified by post-processing the results of a docking screening with BEAR, a recently reported procedure for the refinement and rescoring of docked ligands in virtual screening. FRET substrate degradation assays performed on the 30 most promising compounds resulted in 26 inhibitors with IC(50) values ranging from 4.3 nM to 1.8 microM.Herein we report the discovery of novel and potent inhibitors of Plasmodium falciparum plasmepsin II using GRID computing infrastructures. These compounds were identified by post-processing the results of a large docking screen of commercially available compounds using an automated procedure based on molecular dynamics refinement and binding free-energy estimation using MM-PBSA and MM-GBSA. Among the best-scored compounds, four highly populated and promising chemical classes were identified: N-alkoxyamidines, guanidines, amides, and ureas and thioureas. Thirty hit compounds representative of each class were selected on the basis of their favourable binding free energies and molecular interactions with key active site residues. These were experimentally validated using an inhibition assay based on FRET substrate degradation. Remarkably, 26 of the 30 tested compounds proved to be active as plasmepsin II inhibitors, with IC(50) values ranging from 4.3 nM to 1.8 microM.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1860-7187
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
4
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1164-73
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Design and discovery of plasmepsin II inhibitors using an automated workflow on large-scale grids.
pubmed:affiliation
Dipartimento di Scienze Farmaceutiche, Università di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't