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dc.contributor.authorAntunes, Dinler A.
Devaurs, Didier
Kavraki, Lydia E.
dc.date.accessioned 2016-01-28T17:15:39Z
dc.date.available 2016-01-28T17:15:39Z
dc.date.issued 2015
dc.identifier.citation Antunes, Dinler A., Devaurs, Didier and Kavraki, Lydia E.. "Understanding the challenges of protein flexibility in drug design." Expert Opinion on Drug Discovery, 10, no. 12 (2015) Taylor & Francis: 1301-1313. http://dx.doi.org/10.1517/17460441.2015.1094458.
dc.identifier.urihttps://hdl.handle.net/1911/88215
dc.description.abstract Introduction: Protein–ligand interactions play key roles in various metabolic pathways, and the proteins involved in these interactions represent major targets for drug discovery. Molecular docking is widely used to predict the structure of protein–ligand complexes, and protein flexibility stands out as one of the most important and challenging issues for binding mode prediction. Various docking methods accounting for protein flexibility have been proposed, tackling problems of ever-increasing dimensionality. Areas covered: This paper presents an overview of conformational sampling methods treating target flexibility during molecular docking. Special attention is given to approaches considering full protein flexibility. Contrary to what is frequently done, this review does not rely on classical biomolecular recognition models to classify existing docking methods. Instead, it applies algorithmic considerations, focusing on the level of flexibility accounted for. This review also discusses the diversity of docking applications, from virtual screening (VS) of small drug-like compounds to geometry prediction (GP) of protein–peptide complexes. Expert opinion: Considering the diversity of docking methods presented here, deciding which one is the best at treating protein flexibility depends on the system under study and the research application. In VS experiments, ensemble docking can be used to implicitly account for large-scale conformational changes, and selective docking can additionally consider local binding-site rearrangements. In other cases, on-the-fly exploration of the whole protein–ligand complex might be needed for accurate GP of the binding mode. Among other things, future methods are expected to provide alternative binding modes, which will better reflect the dynamic nature of protein–ligand interactions.
dc.language.iso eng
dc.publisher Taylor & Francis
dc.rights This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Taylor & Francis.
dc.title Understanding the challenges of protein flexibility in drug design
dc.type Journal article
dc.contributor.funder Conselho Nacional de Desenvolvimento Científico e Tecnológico
dc.contributor.funder National Science Foundation
dc.citation.journalTitle Expert Opinion on Drug Discovery
dc.subject.keywordmolecular docking
conformational sampling
protein flexibility
geometry prediction
virtual screening
dc.citation.volumeNumber 10
dc.citation.issueNumber 12
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.1517/17460441.2015.1094458
dc.identifier.grantID CCF 1423304 (National Science Foundation)
dc.identifier.grantID ABI 0960612 (National Science Foundation)
dc.identifier.grantID ABI 1262491 (National Science Foundation)
dc.type.publication post-print
dc.citation.firstpage 1301
dc.citation.lastpage 1313


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