Linked Life Data

19569205

Source:http://linkedlifedata.com/resource/pubmed/id/19569205

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2010-2-3
pubmed:abstractText
In the drug discovery process, accurate methods of computing the affinity of small molecules with a biological target are strongly needed. This is particularly true for molecular docking and virtual screening methods, which use approximated scoring functions and struggle in estimating binding energies in correlation with experimental values. Among the various methods, MM-PBSA and MM-GBSA are emerging as useful and effective approaches. Although these methods are typically applied to large collections of equilibrated structures of protein-ligand complexes sampled during molecular dynamics in water, the possibility to reliably estimate ligand affinity using a single energy-minimized structure and implicit solvation models has not been explored in sufficient detail. Herein, we thoroughly investigate this hypothesis by comparing different methods for the generation of protein-ligand complexes and diverse methods for free energy prediction for their ability to correlate with experimental values. The methods were tested on a series of structurally diverse inhibitors of Plasmodium falciparum DHFR with known binding mode and measured affinities. The results showed that correlations between MM-PBSA or MM-GBSA binding free energies with experimental affinities were in most cases excellent. Importantly, we found that correlations obtained with the use of a single protein-ligand minimized structure and with implicit solvation models were similar to those obtained after averaging over multiple MD snapshots with explicit water molecules, with consequent save of computing time without loss of accuracy. When applied to a virtual screening experiment, such an approach proved to discriminate between true binders and decoy molecules and yielded significantly better enrichment curves.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1096-987X
pubmed:author
pubmed:copyrightInfo
(c) 2009 Wiley Periodicals, Inc.
pubmed:issnType
Electronic
pubmed:volume
31
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
797-810
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Fast and accurate predictions of binding free energies using MM-PBSA and MM-GBSA.
pubmed:affiliation
Dipartimento di Scienze Farmaceutiche, Università di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy. giulio.rastelli@unimore.it
pubmed:publicationType
Journal Article