ArticleProceedings of the National Academy of Sciences of the United States of America2015
Protein design algorithms predict viable resistance to an experimental antifolate.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
What it found
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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
33 citing papers in PubMed, 52 citations in OpenAlex.
- Protocol for DesigningJournal of computational biology : a journal of computational molecular cell biology · 2024Article
- DexDesign: an OSPREY-based algorithm for designing de novo D-peptide inhibitors.Protein engineering, design & selection : PEDS · 2024Article
- RESISTOR: A New OSPREY Module to Predict Resistance Mutations.Journal of computational biology : a journal of computational molecular cell biology · 2022Article
- Article
- Resistor: An algorithm for predicting resistance mutations via Pareto optimization over multistate protein design and mutational signatures.Cell systems · 2022Article
- Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus.PLoS computational biology · 2022Article
- Computer-aided engineering of a branching sucrase for the glucodiversification of a tetrasaccharide precursor of S. flexneri antigenic oligosaccharides.Scientific reports · 2021Article
- A rational blueprint for the design of chemically-controlled protein switches.Nature communications · 2021Article
- High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance.iScience · 2021Article
- Synthetic biology in various cellular and molecular fields: applications, limitations, and perspective.Molecular biology reports · 2020Review
- Novel, provable algorithms for efficient ensemble-based computational protein design and their application to the redesign of the c-Raf-RBD:KRas protein-protein interface.PLoS computational biology · 2020Article
- Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering.International journal of molecular sciences · 2020Review
- Minimization-Aware RecursiveJournal of computational biology : a journal of computational molecular cell biology · 2020Article
- Computational Analysis of Energy Landscapes Reveals Dynamic Features That Contribute to Binding of Inhibitors to CFTR-Associated Ligand.The journal of physical chemistry. B · 2019Article
- Advances in protein structure prediction and design.Nature reviews. Molecular cell biology · 2019Review
- Protein Design by Provable Algorithms.Communications of the ACM · 2019Article
- Article
- Genomics of antibiotic-resistance prediction in Pseudomonas aeruginosa.Annals of the New York Academy of Sciences · 2019Review
- OSPREY 3.0: Open-source protein redesign for you, with powerful new features.Journal of computational chemistry · 2018Article
- Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer.Cell chemical biology · 2018Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Methods to accurately predict potential drug target mutations in response to early-stage leads could drive the design of more resilient first generation drug candidates. In this study, a structure-based protein design algorithm (K* in the OSPREY suite) was used to prospectively identify single-nucleotide polymorphisms that confer resistance to an experimental inhibitor effective against dihydrofolate reductase (DHFR) from Staphylococcus aureus. Four of the top-ranked mutations in DHFR were found to be catalytically competent and resistant to the inhibitor. Selection of resistant bacteria in vitro reveals that two of the predicted mutations arise in the background of a compensatory mutation. Using enzyme kinetics, microbiology, and crystal structures of the complexes, we determined the fitness of the mutant enzymes and strains, the structural basis of resistance, and the compensatory relationship of the mutations. To our knowledge, this work illustrates the first application of protein design algorithms to prospectively predict viable resistance mutations that arise in bacteria under antibiotic pressure.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.