Abstract
Understanding the interactions between activating or antagonizing ligands and their cognate receptors at a molecular level offers promise for the development of pharmacological therapeutics for CNS disorders. The discovery of novel molecules that are capable of discriminating between the varied molecular subunits or isoforms of ion channels should provide a more detailed understanding of the pathophysiology of many CNS disorders. Abundant natural sources of pharmacologically active agents that demonstrate this refined selectivity and specificity are found in the animal toxins of venomous species including: snakes, spiders and the marine snail of the genus Conus. The uniquely fascinating combinatorial ability of the marine snail, genus Conus to modify the pharmacological properties of these neurotoxins or conopeptides within its venom is depicted throughout this review. The myriad of posttranslational modifications and disulfide bonded architectures that have been identified in the conopeptides, are described with an emphasis on the unique pharmacological properties and receptor target specificities that have been ascribed to each of these modifications. The ability of NMR spectroscopy to provide three-dimensional structural information within the interaction interface for both the ligand and target protein following complex formation and its application to conopeptide drug discovery are discussed. Similarly, the strength of merging NMR spectroscopy data with ab initio “;restrained soft-docking” for rational pharmacophore design and the identification of lead compounds from in silico library screens will also be discussed. The initial phases of this stratagem are illustrated using two toxin antagonists and the recently determined structure of the KcsA potassium channel. These data exemplify the utility of this approach in elucidating important molecular interfaces of specific toxin-receptor / ion channel complexes, which can be further exploited in drug discovery initiatives.
Keywords: cone snail, conopeptide, conotoxin, posttranslationally modified amino acids
Current Protein & Peptide Science
Title: Conotoxins and Structural Biology: A Prospective Paradigm for Drug Discovery
Volume: 5 Issue: 4
Author(s): M. A. Grant, X. J. Morelli and A. C. Rigby
Affiliation:
Keywords: cone snail, conopeptide, conotoxin, posttranslationally modified amino acids
Abstract: Understanding the interactions between activating or antagonizing ligands and their cognate receptors at a molecular level offers promise for the development of pharmacological therapeutics for CNS disorders. The discovery of novel molecules that are capable of discriminating between the varied molecular subunits or isoforms of ion channels should provide a more detailed understanding of the pathophysiology of many CNS disorders. Abundant natural sources of pharmacologically active agents that demonstrate this refined selectivity and specificity are found in the animal toxins of venomous species including: snakes, spiders and the marine snail of the genus Conus. The uniquely fascinating combinatorial ability of the marine snail, genus Conus to modify the pharmacological properties of these neurotoxins or conopeptides within its venom is depicted throughout this review. The myriad of posttranslational modifications and disulfide bonded architectures that have been identified in the conopeptides, are described with an emphasis on the unique pharmacological properties and receptor target specificities that have been ascribed to each of these modifications. The ability of NMR spectroscopy to provide three-dimensional structural information within the interaction interface for both the ligand and target protein following complex formation and its application to conopeptide drug discovery are discussed. Similarly, the strength of merging NMR spectroscopy data with ab initio “;restrained soft-docking” for rational pharmacophore design and the identification of lead compounds from in silico library screens will also be discussed. The initial phases of this stratagem are illustrated using two toxin antagonists and the recently determined structure of the KcsA potassium channel. These data exemplify the utility of this approach in elucidating important molecular interfaces of specific toxin-receptor / ion channel complexes, which can be further exploited in drug discovery initiatives.
Export Options
About this article
Cite this article as:
Grant A. M., Morelli J. X. and Rigby C. A., Conotoxins and Structural Biology: A Prospective Paradigm for Drug Discovery, Current Protein & Peptide Science 2004; 5 (4) . https://dx.doi.org/10.2174/1389203043379710
DOI https://dx.doi.org/10.2174/1389203043379710 |
Print ISSN 1389-2037 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5550 |
Call for Papers in Thematic Issues
Advancements in Proteomic and Peptidomic Approaches in Cancer Immunotherapy: Unveiling the Immune Microenvironment
The scope of this thematic issue centers on the integration of proteomic and peptidomic technologies into the field of cancer immunotherapy, with a particular emphasis on exploring the tumor immune microenvironment. This issue aims to gather contributions that illustrate the application of these advanced methodologies in unveiling the complex interplay ...read more
Artificial Intelligence for Protein Research
Protein research, essential for understanding biological processes and creating therapeutics, faces challenges due to the intricate nature of protein structures and functions. Traditional methods are limited in exploring the vast protein sequence space efficiently. Artificial intelligence (AI) and machine learning (ML) offer promising solutions by improving predictions and speeding up ...read more
Nutrition and Metabolism in Musculoskeletal Diseases
The musculoskeletal system consists mainly of cartilage, bone, muscles, tendons, connective tissue and ligaments. Balanced metabolism is of vital importance for the homeostasis of the musculoskeletal system. A series of musculoskeletal diseases (for example, sarcopenia, osteoporosis) are resulted from the dysregulated metabolism of the musculoskeletal system. Furthermore, metabolic diseases (such ...read more
Protein Folding, Aggregation and Liquid-Liquid Phase Separation
Protein folding, misfolding and aggregation remain one of the main problems of interdisciplinary science not only because many questions are still open, but also because they are important from the point of view of practical application. Protein aggregation and formation of fibrillar structures, for example, is a hallmark of a ...read more
Related Journals
- 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
Related Articles
-
Current & Future Therapies of Erectile Dysfunction in Neurological Disorders
Recent Patents on CNS Drug Discovery (Discontinued) Potassium Channels and CNS Diseases
CNS & Neurological Disorders - Drug Targets Marijuana Use in Young Adults: What Do We Know?
Current Psychopharmacology Tailored Multi-Target Agents. Applications and Design Considerations
Current Pharmaceutical Design Placental Drug Disposition and Its Clinical Implications
Current Drug Metabolism Anticancer Mammalian Target of Rapamycin (mTOR) Signaling Pathway Inhibitors: Current Status, Challenges and Future Prospects in Management of Epilepsy
CNS & Neurological Disorders - Drug Targets In Vivo Imaging of the Metabotropic Glutamate Receptor 1 (mGluR1) with Positron Emission Tomography: Recent Advance and Perspective
Current Medicinal Chemistry Antidepressant Brain Stimulation Techniques
Current Psychiatry Reviews Midkine: A Promising Molecule for Drug Development to Treat Diseases of the Central Nervous System
Current Pharmaceutical Design 2-Oxo-1,2,3,4-tetrahydropyrimidines Ethyl Esters as Potent β- Glucuronidase Inhibitors: One-pot Synthesis, In vitro and In silico Studies
Medicinal Chemistry Potential Therapeutic Relevance of Adenosine A2B and A2A Receptors in the Central Nervous System
CNS & Neurological Disorders - Drug Targets Evaluation of Vancoplus Versus Ceftriaxone Against Cephalosporin Resistance MRSA Strain in Experimental Meningitis Model
Cardiovascular & Hematological Disorders-Drug Targets Halogenated Derivatives of Aromatic Amino Acids Exhibit Balanced Antiglutamatergic Actions: Potential Applications for the Treatment of Neurological and Neuropsychiatric Disorders
Recent Patents on CNS Drug Discovery (Discontinued) Induction of Nuclear Receptors and Drug Resistance in the Brain Microvascular Endothelial Cells Treated with Antiepileptic Drugs
Current Neurovascular Research Antiepileptic Treatment Strategy in Vascular Malformations
Current Pharmaceutical Design α7 Nicotinic Acetylcholine Receptor Mediated Neuroprotection in Parkinson’s Disease
Current Drug Targets Ionotropic Glutamate Receptors & CNS Disorders
CNS & Neurological Disorders - Drug Targets Vitamin D Supplementation: A Promising Approach for the Prevention and Treatment of Strokes
Current Drug Targets The Molecular Basis of Conantokin Antagonism of NMDA Receptor Function
Current Drug Targets Drugs, Environmental Factors, Loci and Genes Involved in Nonsyndromic Orofacial Cleft
Current Pharmacogenomics