ArticleChemical biology & drug design2014
Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase.
Article in Chemical biology & drug design, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Structural biology of HIV-1 reverse transcriptase allosteric inhibitors for drug design.Acta pharmaceutica Sinica. B · 2026Review
- Exploring novel HIV-1 reverse transcriptase inhibitors with drug-resistant mutants: A double mutant surprise.Protein science : a publication of the Protein Society · 2023Article
- Recent Advances in the Synthesis and Applications of m-Aryloxy Phenols.Molecules (Basel, Switzerland) · 2023Review
- Towards design of drugs and delivery systems with the Martini coarse-grained model.QRB discovery · 2022Review
- Molecular and cellular studies evaluating a potent 2-cyanoindolizine catechol diether NNRTI targeting wildtype and Y181C mutant HIV-1 reverse transcriptase.Bioorganic & medicinal chemistry letters · 2019Article
- Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV.Antiviral research · 2019Article
- From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection.Molecular pharmacology · 2017Article
- Design, Conformation, and Crystallography of 2-Naphthyl Phenyl Ethers as Potent Anti-HIV Agents.ACS medicinal chemistry letters · 2016Article
- Computer-aided discovery of anti-HIV agents.Bioorganic & medicinal chemistry · 2016Article
- Carbon nanotubes supported tyrosinase in the synthesis of lipophilic hydroxytyrosol and dihydrocaffeoyl catechols with antiviral activity against DNA and RNA viruses.Bioorganic & medicinal chemistry · 2015Article
- Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants.Journal of medicinal chemistry · 2015Article
- Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers.ACS medicinal chemistry letters · 2014Article
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Authors and funding
7 authors.
Funding
Abstract
Using a computationally driven approach, a class of inhibitors with picomolar potency known as the catechol diethers were developed targeting the non-nucleoside-binding pocket of HIV-1 reverse transcriptase. Computational studies suggested that halogen-bonding interactions between the C5 substituent of the inhibitor and backbone carbonyl of conserved residue Pro95 might be important. While the recently reported crystal structures of the reverse transcriptase complexes confirmed the interactions with the non-nucleoside-binding pocket, they revealed the lack of a halogen-bonding interaction with Pro95. To understand the effects of substituents at the C5 position, we determined additional crystal structures with 5-Br and 5-H derivatives. Using comparative structural analysis, we identified several conformations of the ethoxy uracil dependent on the strength of a van der Waals interaction with the Cγ of Pro95 and the C5 substitution. The 5-Cl and 5-F derivatives position the ethoxy uracil to make more hydrogen bonds, whereas the larger 5-Br and smaller 5-H position the ethoxy uracil to make fewer hydrogen bonds. EC50 values correlate with the trends observed in the crystal structures. The influence of C5 substitutions on the ethoxy uracil conformation may have strategic value, as future derivatives can possibly be modulated to gain additional hydrogen-bonding interactions with resistant variants of reverse transcriptase.
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