Abstract
Many enzymes and proteins are regulated by their quaternary structure and/or by their association in homoand/ or hetero-oligomer complexes. Thus, these protein-protein interactions can be good targets for blocking or modulating protein function therapeutically. The large number of oligomeric structures in the Protein Data Bank (http://www.rcsb. org/) reflects growing interest in proteins that function as multimeric complexes. In this review, we consider the particular case of homodimeric enzymes as drug targets. There is intense interest in drugs that inhibit dimerization of a functionally obligate homodimeric enzyme. Because amino acid conservation within enzyme interfaces is often low compared to conservation in active sites, it may be easier to achieve drugs that target protein interfaces selectively and specifically. Two main types of dimerization inhibitors have been developed: peptides or peptidomimetics based on sequences involved in protein-protein interactions, and small molecules that act at hot spots in protein-protein interfaces. Examples include inhibitors of HIV protease and HIV integrase. Studying the mechanisms of action and locating the binding sites of such inhibitors requires different techniques for different proteins. For some enzymes, ligand binding is only detectable in vivo or after unfolding of the complexes. Here, we review the structural features of dimeric enzymes and give examples of inhibition through interference in dimer stability. Several techniques for studying these complex phenomena will be presented.
Keywords: Homodimeric enzyme, dimeric proteins, drug target, protein-protein interactions, inhibitors design, dissociative inhibition model
Current Medicinal Chemistry
Title: Homodimeric Enzymes as Drug Targets
Volume: 17 Issue: 9
Author(s): D. Cardinale, O. M.H. Salo-Ahen, S. Ferrari, G. Ponterini, G. Cruciani, E. Carosati, A. M. Tochowicz, S. Mangani, R. C. Wade and M. P. Costi
Affiliation:
Keywords: Homodimeric enzyme, dimeric proteins, drug target, protein-protein interactions, inhibitors design, dissociative inhibition model
Abstract: Many enzymes and proteins are regulated by their quaternary structure and/or by their association in homoand/ or hetero-oligomer complexes. Thus, these protein-protein interactions can be good targets for blocking or modulating protein function therapeutically. The large number of oligomeric structures in the Protein Data Bank (http://www.rcsb. org/) reflects growing interest in proteins that function as multimeric complexes. In this review, we consider the particular case of homodimeric enzymes as drug targets. There is intense interest in drugs that inhibit dimerization of a functionally obligate homodimeric enzyme. Because amino acid conservation within enzyme interfaces is often low compared to conservation in active sites, it may be easier to achieve drugs that target protein interfaces selectively and specifically. Two main types of dimerization inhibitors have been developed: peptides or peptidomimetics based on sequences involved in protein-protein interactions, and small molecules that act at hot spots in protein-protein interfaces. Examples include inhibitors of HIV protease and HIV integrase. Studying the mechanisms of action and locating the binding sites of such inhibitors requires different techniques for different proteins. For some enzymes, ligand binding is only detectable in vivo or after unfolding of the complexes. Here, we review the structural features of dimeric enzymes and give examples of inhibition through interference in dimer stability. Several techniques for studying these complex phenomena will be presented.
Export Options
About this article
Cite this article as:
Cardinale D., Salo-Ahen M.H. O., Ferrari S., Ponterini G., Cruciani G., Carosati E., Tochowicz M. A., Mangani S., Wade C. R. and Costi P. M., Homodimeric Enzymes as Drug Targets, Current Medicinal Chemistry 2010; 17 (9) . https://dx.doi.org/10.2174/092986710790712156
DOI https://dx.doi.org/10.2174/092986710790712156 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Optimizing Conventional Medical Therapies in Inflammatory Bowel Disease in 2014
Current Drug Targets Editorial [Hot Topic: Anti-Neuroinflammatory Effects of Psychopharmaceuticals: Further than Monoamine Modulators (Guest Editor: Sadayuki Hashioka)]
Mini-Reviews in Medicinal Chemistry Proteoglycans in Inflammation
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents The Therapeutic Potential of Small Activating RNAs for Colorectal Carcinoma
Current Gene Therapy Cannabinoids for the Treatment of Schizophrenia: An Overview
Current Topics in Medicinal Chemistry Disease Outcome, Alexithymia and Depression are Differently Associated with Serum IL-18 Levels in Acute Stroke
Current Neurovascular Research Inflammatory Markers in Essential Hypertension: Potential Clinical Implications
Current Vascular Pharmacology Receptor Tyrosine Kinases: The Main Targets for New Anticancer Therapy
Current Drug Targets Progress in Topical siRNA Delivery Approaches for Skin Disorders
Current Pharmaceutical Design Treatment of Chronic Hepatitis B
Current Pharmaceutical Design Bombesin-like Peptides: Candidates as Diagnostic and Therapeutic Tools
Current Pharmaceutical Design Association of Mean Platelet Volume with Hypertension in Rheumatoid Arthritis
Inflammation & Allergy - Drug Targets (Discontinued) Polyphenol Supplementation as a Complementary Medicinal Approach to Treating Inflammatory Bowel Disease
Current Medicinal Chemistry Inflammaging in Skin and other Tissues - The Roles of Complement System and Macrophage
Inflammation & Allergy - Drug Targets (Discontinued) Butyrate and Colorectal Cancer: The Role of Butyrate Transport
Current Drug Metabolism Reprogramming Cancer Cells in Endocrine-Related Tumors: Open Issues
Current Medicinal Chemistry Identification of Novel Drug Targets for Angiostatic Cancer Therapy; It Takes Two to Tango
Current Pharmaceutical Design Creating A Standard of Care for Fertility Preservation
Current Women`s Health Reviews Recent Advances in Substrate Identification of Protein Kinases in Plants and Their Role in Stress Management
Current Genomics Emerging Novel Treatment Strategies for Diabetic Eye Diseases
Current Diabetes Reviews