Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 1
| Autor: | Richard J. Hazen, Joseph H. Chan, David K. Stammers, Jingshan Ren, David I. Stuart, John Milton, Andrew L. Hopkins |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular medicine.drug_class Anti-HIV Agents Drug resistance Quinolones medicine.disease_cause Crystallography X-Ray Cell Line Structure-Activity Relationship Drug Discovery Drug Resistance Viral medicine Structure–activity relationship Humans Mutation Reverse-transcriptase inhibitor Molecular Structure Chemistry virus diseases Nucleotidyltransferase Quinolone Reverse transcriptase HIV Reverse Transcriptase Biochemistry Drug Design HIV-1 Molecular Medicine Reverse Transcriptase Inhibitors Nucleoside medicine.drug |
| Popis: | We have used a structure-based approach to design a novel series of non-nucleoside inhibitors of HIV-1 RT (NNRTIs). Detailed analysis of a wide range of crystal structures of HIV-1 RT-NNRTI complexes together with data on drug resistance mutations has identified factors important for tight binding of inhibitors and resilience to mutations. Using this approach we have designed and synthesized a novel series of quinolone NNRTIs. Crystal structure analysis of four of these compounds in complexes with HIV-1 RT confirms the predicted binding modes. Members of this quinolone series retain high activity against the important resistance mutations in RT at Tyr181Cys and Leu100Ile. |
| Databáze: | OpenAIRE |
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