ArticleCell chemical biology2019
Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins.
Article in Cell chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Discovery of the microtubule-severing protein as the target of antifungal compound heat-stable antifungal factor in Fusarium graminearum and rational design of novel inhibitors.Pest management science · 2026Article
- CaMKIIβ-mediated Phosphorylation Enhances Protein Stability of Spastin to Promote Neurite Outgrowth.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Covalent adduct Grob fragmentation underlies LSD1 demethylase-specific inhibitor mechanism of action and resistance.Nature communications · 2025Article
- Investigation into the Potential Mechanism of Radix Paeoniae Rubra Against Ischemic Stroke Based on Network Pharmacology.Nutrients · 2024Article
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- Allosteric activation of VCP, an AAA unfoldase, by small molecule mimicry.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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- Achieving the promise and avoiding the peril of chemical probes using genetics.Current opinion in structural biology · 2023Review
- Assessing the influence of industry 4.0 technologies on occupational health and safety.Heliyon · 2023Article
- Discovering new biology with drug-resistance alleles.Nature chemical biology · 2021Review
- AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors.European journal of medicinal chemistry · 2021Review
- A chemical genetics approach to examine the functions of AAA proteins.Nature structural & molecular biology · 2021Article
- Article
- Exploring Ovarian Cancer Cell Resistance to Rhenium Anticancer Complexes.Angewandte Chemie (International ed. in English) · 2020Article
- Exploring ovarian cancer cell resistance to rhenium anticancer complexes.Angewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2020Article
- Ploidy Leads a Molecular Motor to Walk Different Paths to Drug Resistance.Cell chemical biology · 2020Article
- Distinct Mechanisms of Resistance to a CENP-E Inhibitor Emerge in Near-Haploid and Diploid Cancer Cells.Cell chemical biology · 2020Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
Drug-like inhibitors are often designed by mimicking cofactor or substrate interactions with enzymes. However, as active sites are comprised of conserved residues, it is difficult to identify the critical interactions needed to design selective inhibitors. We are developing an approach, named RADD (resistance analysis during design), which involves engineering point mutations in the target to generate active alleles and testing compounds against them. Mutations that alter compound potency identify residues that make key interactions with the inhibitor and predict target-binding poses. Here, we apply this approach to analyze how diaminotriazole-based inhibitors bind spastin, a microtubule-severing AAA (ATPase associated with diverse cellular activities) protein. The distinct binding poses predicted for two similar inhibitors were confirmed by a series of X-ray structures. Importantly, our approach not only reveals how selective inhibition of the target can be achieved but also identifies resistance-conferring mutations at the early stages of the design process.
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Registered trials
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