Abstract
Monte Carlo simulations using free energy perturbation theory have been used to guide the selection of bicyclic heterocycles in the lead optimization of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Good correlation is found between predicted and observed activities. Six compounds are reported with EC50 values below 20 nM for protection of human MT-2 cells against the cytopathogenicity of HIV-1. Striking variation in activity is found and analyzed for an isomeric pyrrolopyrimidine and pyrrolopyrazine pair.
Publication types
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Research Support, N.I.H., Extramural
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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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Drug Design
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HIV Reverse Transcriptase / antagonists & inhibitors*
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Models, Molecular
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Molecular Structure
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Nanostructures
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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
Substances
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Anti-HIV Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Reverse Transcriptase Inhibitors
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HIV Reverse Transcriptase