Abstract
The targeting of non-catalytic cysteine residues with small molecules is drawing increased attention from drug discovery scientists and chemical biologists. From a biological perspective, genomic and proteomic studies have revealed the presence of cysteine mutations in several oncogenic proteins, suggesting both a functional role for these residues and also a strategy for targeting them in an ‘allele specific’ manner. For the medicinal chemist, the structure-guided design of cysteine- reactive molecules is an appealing strategy to realize improved selectivity and pharmacodynamic properties in drug leads. Finally, for chemical biologists, the modification of cysteine residues provides a unique means to probe protein structure and allosteric regulation. Here, we review three applications of cysteinemodifying small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead compounds, and 3) the use of cysteine-reactive molecules as probes of protein dynamics. In each case, structure-guided design plays a key role in determining which cysteine residue(s) to target and in designing compounds with the proper geometry to enable both covalent interaction with the targeted cysteine and productive non-covalent interactions with nearby protein residues.
Keywords: Non-catalytic cysteine, Covalent drugs, Structure-based design, Chemical probes, disulfide Tethering, Lead optimization, Protein dynamics, Protein allostery.
Current Topics in Medicinal Chemistry
Title:Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery
Volume: 17 Issue: 1
Author(s): Kenneth K. Hallenbeck, David M. Turner, Adam R. Renslo and Michelle R. Arkin
Affiliation:
Keywords: Non-catalytic cysteine, Covalent drugs, Structure-based design, Chemical probes, disulfide Tethering, Lead optimization, Protein dynamics, Protein allostery.
Abstract: The targeting of non-catalytic cysteine residues with small molecules is drawing increased attention from drug discovery scientists and chemical biologists. From a biological perspective, genomic and proteomic studies have revealed the presence of cysteine mutations in several oncogenic proteins, suggesting both a functional role for these residues and also a strategy for targeting them in an ‘allele specific’ manner. For the medicinal chemist, the structure-guided design of cysteine- reactive molecules is an appealing strategy to realize improved selectivity and pharmacodynamic properties in drug leads. Finally, for chemical biologists, the modification of cysteine residues provides a unique means to probe protein structure and allosteric regulation. Here, we review three applications of cysteinemodifying small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead compounds, and 3) the use of cysteine-reactive molecules as probes of protein dynamics. In each case, structure-guided design plays a key role in determining which cysteine residue(s) to target and in designing compounds with the proper geometry to enable both covalent interaction with the targeted cysteine and productive non-covalent interactions with nearby protein residues.
Export Options
About this article
Cite this article as:
Hallenbeck K. Kenneth, Turner M. David, Renslo R. Adam and Arkin R. Michelle, Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery, Current Topics in Medicinal Chemistry 2017; 17 (1) . https://dx.doi.org/10.2174/1568026616666160719163839
DOI https://dx.doi.org/10.2174/1568026616666160719163839 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The p53-p66Shc Apoptotic Pathway is Dispensable for Tumor Suppression whereas the p66Shc-generated Oxidative Stress Initiates Tumorigenesis
Current Pharmaceutical Design STAT3: A Molecular Target for Cancer Whose Time Has Come
Current Signal Transduction Therapy Isoprenylation of Intracellular Proteins as a New Target for the Therapy of Human Neoplasms: Preclinical and Clinical Implications
Current Drug Targets Therapeutic Nucleic Acids
Recent Patents on Regenerative Medicine Promoters and Control Elements: Designing Expression Cassettes for Gene Therapy
Current Gene Therapy Nucleocytoplasmic Glycosylation, O-linked β-N-Acetylglucosamine
Current Organic Chemistry The Role of Major Histocompatibility Complex Polymorphisms in the Incidence and Outcome of Non-Hodgkin Lymphoma
Current Immunology Reviews (Discontinued) NFAT Gene Family in Inflammation and Cancer
Current Molecular Medicine Progress Toward Vector Design for Hematopoietic Stem Cell Gene Therapy
Current Gene Therapy Review of Recent Clinical Developments and Patents for the Treatment of Autoimmune and Inflammatory Diseases by Mesenchymal Stromal Cells
Recent Patents on Regenerative Medicine Reverse Pharmacognosy: Another Way to Harness the Generosity of Nature
Current Pharmaceutical Design Cancer Stem Cells: How can we Target them?
Current Medicinal Chemistry Emerging Targets For Prostate Adenocarcinoma Therapy: How Molecular Biology May Drive Towards a More Tailored Approach
Current Drug Targets 3-Substituted Isocoumarins as Thymidine Phosphorylase Inhibitors
Letters in Drug Design & Discovery Nanotech Revolution for the Anti-Cancer Drug Delivery through Blood- Brain-Barrier
Current Cancer Drug Targets Expression and Characterisation of Recombinant Molecules in Transgenic Soybean
Current Pharmaceutical Design Role of Angiopoietin-like 4 (ANGPTL4), a Member of Matricellular Proteins: from Homeostasis to Inflammation and Cancer Metastasis
Current Angiogenesis (Discontinued) Targeted Therapies in Solid Tumours: Pinpointing the Tumours Achilles Heel
Current Pharmaceutical Design Papillary Thyroid Carcinoma in Pediatric Age: An Example of a Rare Tumour Managed Within a Cooperative Comprehensive Project
Current Pediatric Reviews Long-circulating Targeted Nanoparticles for Cancer Therapy
Current Nanoscience