ArticleJournal of medicinal chemistry2015
Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants.
Article in Journal of medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed.
- Medicinal Chemistry Aspects of Thiazole and Thiazolidine Derivatives as Fundamental Building Blocks to Design New NNRTIs Against HIV-1 Reverse Transcriptase.ChemMedChem · 2026Review
- Prevalence and mobile genetic element-mediated dissemination of antimicrobial resistance along the swine industry chain of Guizhou, China.BMC veterinary research · 2026Article
- Accelerated Combinatorial Drug Design for Human Immunodeficiency Virus Resistance through Seeded Multisite λ-Dynamics.Journal of chemical theory and computation · 2026Article
- Structural biology of HIV-1 reverse transcriptase allosteric inhibitors for drug design.Acta pharmaceutica Sinica. B · 2026Review
- Late-stage modification of bioactive compounds: Improving druggability through efficient molecular editing.Acta pharmaceutica Sinica. B · 2024Review
- Exploring novel HIV-1 reverse transcriptase inhibitors with drug-resistant mutants: A double mutant surprise.Protein science : a publication of the Protein Society · 2023Article
- Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs).Viruses · 2023Review
- Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties.Journal of medicinal chemistry · 2023Article
- Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase.Frontiers in molecular biosciences · 2022Article
- The Fellowship of Privileged Scaffolds-One Structure to Inhibit Them All.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Structural investigation of 2-naphthyl phenyl ether inhibitors bound to WT and Y181C reverse transcriptase highlights key features of the NNRTI binding site.Protein science : a publication of the Protein Society · 2020Article
- 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
- The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic.Journal of medicinal chemistry · 2019Article
- Multiple Machine Learning Comparisons of HIV Cell-based and Reverse Transcriptase Data Sets.Molecular pharmaceutics · 2019Article
- Diaryl ethers with carboxymethoxyphenacyl motif as potent HIV-1 reverse transcriptase inhibitors with improved solubility.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Article
- Predicting Binding Free Energies in a Large Combinatorial Chemical Space Using Multisite λ Dynamics.The journal of physical chemistry letters · 2018Article
- Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection.Molecular pharmacology · 2017Article
- The "Sticky Patch" Model of Crystallization and Modification of Proteins for Enhanced Crystallizability.Methods in molecular biology (Clifton, N.J.) · 2017Review
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants of HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. The NNRTIs bind in an allosteric pocket in RT ∼10 Å away from the active site. Earlier analogues of the catechol diether compound series have picomolar activity against HIV strains with wild-type RT but lose potency against variants with single Y181C and double K103N/Y181C mutations. As guided by structure-based and computational studies, removal of the 5-Cl substitution of compound 1 on the catechol aryl ring system led to a new analogue compound 2 that maintains greater potency against Y181C and K103N/Y181C variants and better solubility (510 μg/mL). Crystal structures were determined for wild-type, Y181C, and K103N/Y181C RT in complex with both compounds 1 and 2 to understand the structural basis for these findings. Comparison of the structures reveals that the Y181C mutation destabilizes the binding mode of compound 1 and disrupts the interactions with residues in the pocket. Compound 2 maintains the same conformation in wild-type and mutant structures, in addition to several interactions with the NNRTI binding pocket. Comparison of the six crystal structures will assist in the understanding of compound binding modes and future optimization of the catechol diether series.
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