Abstract
The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site. The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics. The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519:131-143). Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor α. Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics.
Keywords: HIV integrase, morpheein, phenylalanine hydroxylase, porphobilinogen synthase, pyruvate kinase, transthyretin, tumor necrosis factor alpha, protein dynamics
Current Topics in Medicinal Chemistry
Title:Impact of Quaternary Structure Dynamics on Allosteric Drug Discovery
Volume: 13 Issue: 1
Author(s): Eileen K. Jaffe
Affiliation:
Keywords: HIV integrase, morpheein, phenylalanine hydroxylase, porphobilinogen synthase, pyruvate kinase, transthyretin, tumor necrosis factor alpha, protein dynamics
Abstract: The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site. The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics. The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519:131-143). Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor α. Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics.
Export Options
About this article
Cite this article as:
K. Jaffe Eileen, Impact of Quaternary Structure Dynamics on Allosteric Drug Discovery, Current Topics in Medicinal Chemistry 2013; 13 (1) . https://dx.doi.org/10.2174/1568026611313010006
DOI https://dx.doi.org/10.2174/1568026611313010006 |
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
-
Herpesvirus Saimiri-Based Gene Delivery Vectors
Current Gene Therapy Carbohydrate-Metal Complexes and their Potential as Anticancer Agents
Current Medicinal Chemistry The Functions of Histone Modification Enzymes in Cancer
Current Protein & Peptide Science Wide-Ranging Genomic Effects of Plasticisers and Related Compounds
Current Drug Metabolism Involvement of Targeting and Scaffolding Proteins in the Regulation of the EGFR/Ras/MAPK Pathway in Oncogenesis
Current Signal Transduction Therapy Optimization of Lentiviral Vectors Generation for Biomedical and Clinical Research Purposes: Contemporary Trends in Technology Development and Applications
Current Gene Therapy Targeting Sphingosine-1-Phosphate Receptors in Cancer
Anti-Cancer Agents in Medicinal Chemistry Anatomical Approach to Clinical Problems of Popliteal Fossa
Current Rheumatology Reviews Forms of Iron Binding in the Cells and the Chemical Features of Chelation Therapy
Mini-Reviews in Medicinal Chemistry Recent Advances in the Discovery of Novel HSP90 Inhibitors: An Update from 2014
Current Drug Targets Novel Molecular Targets and Mechanisms Involved in the Invasion and Metastasis of Pancreatic Cancer
Clinical Cancer Drugs Role of Transforming Growth Factor Beta in Corneal Function, Biology and Pathology
Current Molecular Medicine Biosafety of Lentiviral Vectors
Current Gene Therapy Pharmacological Interventions for the Prevention and Treatment of Kidney Injury Induced by Radiotherapy: Molecular Mechanisms and Clinical Perspectives
Current Molecular Pharmacology Insertional Mutagenesis by Retroviral Vectors: Current Concepts and Methods of Analysis
Current Gene Therapy The Roles of the Unique Prolyl Isomerase Pin1 in Cancer-Related Viral and Bacterial Infections
Current Molecular Medicine The Therapeutic Potential of ADAM15
Current Pharmaceutical Design Fertility Preservation in Women After the Cancer
Current Pharmaceutical Design Biomarkers in Amyotrophic Lateral Sclerosis: Is There A Neurovascular Pathway?
Current Neurovascular Research Apoptosis-Inducing Effects of Amaryllidaceae Alkaloids
Current Medicinal Chemistry