Abstract
Non-synonymous single nucleotide polymorphisms (nsSNPs) are genetic variations that affect the encoded protein by an amino acid change. In humans, many naturally-occurring nsSNPs cause protein dysfunction and increase vulnerability to disease. Identification of such nsSNPs provides an important opportunity to develop drugs/nutrients with precise therapeutic targets. Therefore, current biomedical research and medicinal chemistry look for targets and functional nsSNPs, to establish correlation with disease susceptibility and foster rational drug design. We review the molecular bases of missense mutation effects at the protein level, namely on sequence conservation, including stability, conformation, biophysical parameters, and protein-protein interaction. Further, we summarize some computational methods, available information resources, and the current approaches used to predict nsSNPs functionality in human genome, most of which based on protein structures and/or evolutionary conservation. Finally, using an approach paradigmatic of the nsSNPs-gene interactions, we evaluate the functional consequences and phenotypic effects of nsSNPs on two genes associated with cholesterol response. Biophysical changes produced by exchanged amino acids I638V (rs5908) from the 3-hydroxy-3-methylglutaryl- coenzyme A reductase gene, and A370T (rs11669576) from the low density lipoprotein receptor gene have been analyzed with an emphasis on stability, activity, and structure of their related proteins. Based on available data and the results of our study, we propose that, even though the extent and precise nature of nsSNPs role in health and disease is yet to be fully elucidated, targeted investigations are warranted and will – in the future – provide useful tools to develop targeted drugs.
Keywords: Cholesterol, disease, gene, HMGCR, LDLR, non-synonymous single nucleotide polymorphisms, protein structure, protein sequence, structural genomics, functional genomics
Current Medicinal Chemistry
Title: Functional Non-Synonymous Polymorphisms Prediction Methods: Current Approaches and Future Developments
Volume: 18 Issue: 33
Author(s): M. Gonzalez-Castejon, F. Marin, C. Soler-Rivas, G. Reglero, F. Visioli and A. Rodriguez-Casado
Affiliation:
Keywords: Cholesterol, disease, gene, HMGCR, LDLR, non-synonymous single nucleotide polymorphisms, protein structure, protein sequence, structural genomics, functional genomics
Abstract: Non-synonymous single nucleotide polymorphisms (nsSNPs) are genetic variations that affect the encoded protein by an amino acid change. In humans, many naturally-occurring nsSNPs cause protein dysfunction and increase vulnerability to disease. Identification of such nsSNPs provides an important opportunity to develop drugs/nutrients with precise therapeutic targets. Therefore, current biomedical research and medicinal chemistry look for targets and functional nsSNPs, to establish correlation with disease susceptibility and foster rational drug design. We review the molecular bases of missense mutation effects at the protein level, namely on sequence conservation, including stability, conformation, biophysical parameters, and protein-protein interaction. Further, we summarize some computational methods, available information resources, and the current approaches used to predict nsSNPs functionality in human genome, most of which based on protein structures and/or evolutionary conservation. Finally, using an approach paradigmatic of the nsSNPs-gene interactions, we evaluate the functional consequences and phenotypic effects of nsSNPs on two genes associated with cholesterol response. Biophysical changes produced by exchanged amino acids I638V (rs5908) from the 3-hydroxy-3-methylglutaryl- coenzyme A reductase gene, and A370T (rs11669576) from the low density lipoprotein receptor gene have been analyzed with an emphasis on stability, activity, and structure of their related proteins. Based on available data and the results of our study, we propose that, even though the extent and precise nature of nsSNPs role in health and disease is yet to be fully elucidated, targeted investigations are warranted and will – in the future – provide useful tools to develop targeted drugs.
Export Options
About this article
Cite this article as:
Gonzalez-Castejon M., Marin F., Soler-Rivas C., Reglero G., Visioli F. and Rodriguez-Casado A., Functional Non-Synonymous Polymorphisms Prediction Methods: Current Approaches and Future Developments, Current Medicinal Chemistry 2011; 18 (33) . https://dx.doi.org/10.2174/092986711797636081
DOI https://dx.doi.org/10.2174/092986711797636081 |
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
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...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
- 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
-
Covid-19: An Update on Clinical Features, Diagnosis, and Treatment Strategies
Coronaviruses Lipids, Statins and Heart Failure: An Update
Current Pharmaceutical Design Signal Transduction of Steroidogenic Hormones to the Adrenal and Gonadal Mitochondria and the Possibilities for Combating Lipoid Congenital Adrenal Hyperplasia
Current Signal Transduction Therapy Bispidine as a Privileged Scaffold
Current Topics in Medicinal Chemistry Carbohydrate based Potential Chemotherapeutic Agents: Recent Developments and their Scope in Future Drug Discovery
Mini-Reviews in Medicinal Chemistry Green Tea Polyphenols as an Anti-Oxidant and Anti-Inflammatory Agent for Cardiovascular Protection
Cardiovascular & Hematological Disorders-Drug Targets New Inotropic Pharmacologic Strategies Targeting the Failing Myocardiumin the Newborn and Infant
Mini-Reviews in Medicinal Chemistry Preparation and Characterization of Water-soluble and Highly Fluorescent Biopolymer-conjugated CdS Quantum Dots
Current Nanoscience The Development of Antibody-based Immunotherapy for Methamphetamine Abuse: Immunization, and Virus-Mediated Gene Transfer Approaches
Current Gene Therapy Sleep Loss and Hypertension: A Systematic Review
Current Pharmaceutical Design Postprandial Hypertriglyceridaemia Revisited in the Era of Non-Fasting Lipid Profile Testing: A 2019 Expert Panel Statement, Main Text
Current Vascular Pharmacology Phytochemicals and Antioxidants: An Evaluation in Understanding the Human Lifeline
Current Nutrition & Food Science Tianeptine: A Novel Atypical Antidepressant that May Provide New Insights into the Biomolecular Basis of Depression
Recent Patents on CNS Drug Discovery (Discontinued) Abdominal Aortic Calcification: Clinical Significance, Mechanisms and Therapies
Current Pharmaceutical Design Editorial (Thematic Issues: Autoimmunity and Autoinflammation: Cardiovascular Drug Targets and Design)
Current Pharmaceutical Design The Role of COX-2 in Heart Pathology
Cardiovascular & Hematological Agents in Medicinal Chemistry Autoimmune Hepatitis: Pathophysiology, Diagnosis and Pharmacological Therapy
Current Immunology Reviews (Discontinued) Heat Shock Proteins - Two Sides of a Coin
Current Cardiology Reviews An Overview on COVID-19 and its Effect on Cardiovascular Diseases
Endocrine, Metabolic & Immune Disorders - Drug Targets Subject Index to Volume 9
Current Pharmaceutical Design