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
-
Role of Vitamin D in Vascular Complications and Vascular Access Outcome in Patients with Chronic Kidney Disease
Current Medicinal Chemistry Matrix Metalloproteinases as Potential Targets in the Venous Dilation Associated with Varicose Veins
Current Drug Targets Targeted Nanosystems to Prostate Cancer
Current Pharmaceutical Design Predictive Efficacy Biomarkers of Programmed Cell Death 1/Programmed Cell Death 1 Ligand Blockade Therapy
Recent Patents on Anti-Cancer Drug Discovery ErbB4 and its Isoforms: Patentable Drug Targets?
Recent Patents on DNA & Gene Sequences Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets
Anti-Cancer Agents in Medicinal Chemistry Recent Progress in Chemically Modified siRNAs
Mini-Reviews in Medicinal Chemistry Thiosemicarbazones as Potent Anticancer Agents and their Modes of Action
Mini-Reviews in Medicinal Chemistry Galectin-9 in Cancer Therapy
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Persistent Current Blockers of Voltage-Gated Sodium Channels: A Clinical Opportunity for Controlling Metastatic Disease
Recent Patents on Anti-Cancer Drug Discovery Identification of Novel Drug Targets for Angiostatic Cancer Therapy; It Takes Two to Tango
Current Pharmaceutical Design Physiologically Based Pharmacokinetic Models: Integration of In Silico Approaches with Micro Cell Culture Analogues
Current Drug Metabolism Non-Camptothecin DNA Topoisomerase I Inhibitors in Cancer Therapy
Current Topics in Medicinal Chemistry RETRACTED: Novel and safer self-inactivating vectors for gene therapy of Wiskott-Aldrich Syndrome
Current Gene Therapy Fig Latex (Ficus carica L. cultivar Dottato) in Combination with UV Irradiation Decreases the Viability of A375 Melanoma Cells In Vitro
Anti-Cancer Agents in Medicinal Chemistry Glycoconjugates in Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Coordinated Expression of Pax-5 and FAK1 in Metastasis
Anti-Cancer Agents in Medicinal Chemistry Writers and Erasers of Histone Lysine methylation with Clinically Applied Modulators: Promising Target for Cancer Therapy
Current Pharmaceutical Design Targeted Cancer Therapy; Nanotechnology Approaches for Overcoming Drug Resistance
Current Medicinal Chemistry Cardiotonic Steroids, Hypertension and Cardiovascular Disease
Current Hypertension Reviews