Abstract
Because HIV-1 reverse transcriptase is an enzyme whose catalytic activity depends on its heterodimeric structure, this system could be a target for inhibitors that perturb the interactions between the protein subunits, p51 and p66. We previously demonstrated that the small molecule MAS0 reduced the association of the two RT subunits and simultaneously inhibited both the polymerase and ribonuclease H activities. In this study, some analogues of MAS0 were rationally selected by docking studies and evaluated in vitro for their ability to disrupt dimeric assembly. Two inhibitors were identified with improved activity compared to MAS0. This study lays the basis for the rational design of more potent inhibitors of RT dimerization.
Keywords:
HIV-1 reverse transcriptase; dimerization inhibitors; protein-protein interaction; virtual screening; viruses.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology*
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Enzyme Activation / drug effects
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Enzyme Stability / drug effects
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HIV / drug effects*
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HIV / enzymology*
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / metabolism
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Models, Molecular
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Molecular Structure
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Protein Multimerization / drug effects
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology*
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Temperature
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Virus Replication / drug effects
Substances
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Anti-HIV Agents
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Reverse Transcriptase Inhibitors
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Small Molecule Libraries
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase