Binding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study.

2.50
Hdl Handle:
http://hdl.handle.net/10547/228932
Title:
Binding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study.
Authors:
Huang, Meilan; Grant, Guy H.; Richards, W. Graham
Abstract:
HIV-1 integrase (IN) has become an attractive target since drug resistance against HIV-1 reverse transcriptase (RT) and protease (PR) has appeared. Diketo acid (DKA) inhibitors are potent and selective inhibitors of HIV-1 IN: however the action mechanism is not well understood. Here, to study the inhibition mechanism of DKAs we performed 10 ns comparative molecular dynamics simulations on HIV-1 IN bound with three most representative DKA inhibitors: Shionogi inhibitor, S-1360 and two Merck inhibitors L-731,988 and L-708,906. Our simulations show that the acidic part of S-1360 formed salt bridge and cation-π interactions with Lys159. In addition, the catalytic Glu152 in S-1360 was pushed away from the active site to form an ion-pair interaction with Arg199. The Merck inhibitors can maintain either one or both of these ion-pair interaction features. The difference in potencies of the DKA inhibitors is thus attributed to the different binding modes at the catalytic site. Such structural information at atomic level, not only demonstrates the action modes of DKA inhibitors but also provides a novel starting point for structural-based design of HIV-1 IN inhibitors.
Affiliation:
School of Chemistry and Chemical Engineering, David Keir Building, Queens University Belfast, Stranmillis Road, Belfast BT95AG, UK. m.huang@qub.ac.uk
Citation:
Binding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study. 2011, 29 (7):956-64 J. Mol. Graph. Model.
Publisher:
Elsevier
Journal:
Journal of molecular graphics & modelling
Issue Date:
Jun-2011
URI:
http://hdl.handle.net/10547/228932
DOI:
10.1016/j.jmgm.2011.04.002
PubMed ID:
21531158
Additional Links:
http://www.ncbi.nlm.nih.gov/pubmed/21531158
Type:
Article
Language:
en
ISSN:
1873-4243
Appears in Collections:
Cell and Cryobiology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorHuang, Meilanen_GB
dc.contributor.authorGrant, Guy H.en_GB
dc.contributor.authorRichards, W. Grahamen_GB
dc.date.accessioned2012-06-14T10:40:24Z-
dc.date.available2012-06-14T10:40:24Z-
dc.date.issued2011-06-
dc.identifier.citationBinding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study. 2011, 29 (7):956-64 J. Mol. Graph. Model.en_GB
dc.identifier.issn1873-4243-
dc.identifier.pmid21531158-
dc.identifier.doi10.1016/j.jmgm.2011.04.002-
dc.identifier.urihttp://hdl.handle.net/10547/228932-
dc.description.abstractHIV-1 integrase (IN) has become an attractive target since drug resistance against HIV-1 reverse transcriptase (RT) and protease (PR) has appeared. Diketo acid (DKA) inhibitors are potent and selective inhibitors of HIV-1 IN: however the action mechanism is not well understood. Here, to study the inhibition mechanism of DKAs we performed 10 ns comparative molecular dynamics simulations on HIV-1 IN bound with three most representative DKA inhibitors: Shionogi inhibitor, S-1360 and two Merck inhibitors L-731,988 and L-708,906. Our simulations show that the acidic part of S-1360 formed salt bridge and cation-π interactions with Lys159. In addition, the catalytic Glu152 in S-1360 was pushed away from the active site to form an ion-pair interaction with Arg199. The Merck inhibitors can maintain either one or both of these ion-pair interaction features. The difference in potencies of the DKA inhibitors is thus attributed to the different binding modes at the catalytic site. Such structural information at atomic level, not only demonstrates the action modes of DKA inhibitors but also provides a novel starting point for structural-based design of HIV-1 IN inhibitors.en_GB
dc.language.isoenen
dc.publisherElsevieren_GB
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/21531158en_GB
dc.rightsArchived with thanks to Journal of molecular graphics & modellingen_GB
dc.subject.meshHIV Integrase-
dc.subject.meshHIV Integrase Inhibitors-
dc.subject.meshHumans-
dc.subject.meshModels, Molecular-
dc.subject.meshMolecular Dynamics Simulation-
dc.subject.meshMolecular Structure-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Conformation-
dc.titleBinding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study.en
dc.typeArticleen
dc.contributor.departmentSchool of Chemistry and Chemical Engineering, David Keir Building, Queens University Belfast, Stranmillis Road, Belfast BT95AG, UK. m.huang@qub.ac.uken_GB
dc.identifier.journalJournal of molecular graphics & modellingen_GB

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