Abstract
Guanine-rich sequences found in telomeres and oncogene promoters have the ability to form G-quadruplex structures. In this paper we describe the use of a virtual screening assay to search a database of FDA-approved compounds for compounds with the potential to bind G-quadruplex DNA. More than 750 telomerase inhibitors were identified in a literature search as acting through G-quadruplex stabilization, and from evaluation of these compounds, theoretical models capable of discriminating new compounds that bind Gquadruplex DNA were developed. Six compounds predicted to bind to the G-quadruplex structure were tested for their ability to bind to the human telomeric DNA sequence. Prochloroperazine, promazine, and chlorpromazine stabilized the G-quadruplex structure as determined by fluorescence resonance energy transfer techniques. These compounds also bound to promoter sequences of oncogenes such as c-myc and K-ras. Amitriptyline, imipramine, and loxapine were less stabilizing but did bind to the G-quadruplex. The ability of prochloroperazine, promazine, and chlorpromazine to recognize G-quadruplex structures was confirmed using a fluorescent intercalator displacement assay, in which displacement of thiazole orange from G-quadruplex structures was demonstrated. Interestingly, these compounds exhibited selectivity for the G-quadruplex structure as all had poor affinity for the duplex sequence.
Keywords: FRET melting, G-quadruplex, QSAR, telomeres, virtual screening, oncogene promoters, FDA-approved compounds, prochloroperazine, promazine, duplex sequence
Current Pharmaceutical Design
Title:FDA-approved Drugs Selected Using Virtual Screening Bind Specifically to G-quadruplex DNA
Volume: 19 Issue: 12
Author(s): Daimel Castillo-Gonzalez, Gisselle Perez-Machado, Aurore Guedin, Jean-Louis Mergny and Miguel-Angel Cabrera-Perez
Affiliation:
Keywords: FRET melting, G-quadruplex, QSAR, telomeres, virtual screening, oncogene promoters, FDA-approved compounds, prochloroperazine, promazine, duplex sequence
Abstract: Guanine-rich sequences found in telomeres and oncogene promoters have the ability to form G-quadruplex structures. In this paper we describe the use of a virtual screening assay to search a database of FDA-approved compounds for compounds with the potential to bind G-quadruplex DNA. More than 750 telomerase inhibitors were identified in a literature search as acting through G-quadruplex stabilization, and from evaluation of these compounds, theoretical models capable of discriminating new compounds that bind Gquadruplex DNA were developed. Six compounds predicted to bind to the G-quadruplex structure were tested for their ability to bind to the human telomeric DNA sequence. Prochloroperazine, promazine, and chlorpromazine stabilized the G-quadruplex structure as determined by fluorescence resonance energy transfer techniques. These compounds also bound to promoter sequences of oncogenes such as c-myc and K-ras. Amitriptyline, imipramine, and loxapine were less stabilizing but did bind to the G-quadruplex. The ability of prochloroperazine, promazine, and chlorpromazine to recognize G-quadruplex structures was confirmed using a fluorescent intercalator displacement assay, in which displacement of thiazole orange from G-quadruplex structures was demonstrated. Interestingly, these compounds exhibited selectivity for the G-quadruplex structure as all had poor affinity for the duplex sequence.
Export Options
About this article
Cite this article as:
Castillo-Gonzalez Daimel, Perez-Machado Gisselle, Guedin Aurore, Mergny Jean-Louis and Cabrera-Perez Miguel-Angel, FDA-approved Drugs Selected Using Virtual Screening Bind Specifically to G-quadruplex DNA, Current Pharmaceutical Design 2013; 19 (12) . https://dx.doi.org/10.2174/1381612811319120004
DOI https://dx.doi.org/10.2174/1381612811319120004 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Novel Anti-Inflammatory and Neuroprotective Agents for Parkinsons Disease
CNS & Neurological Disorders - Drug Targets Growth of Diabetes Research in United Arab Emirates: Current and Future Perspectives
Current Diabetes Reviews 2-Amino/Azido/Hydrazino-5-alkoxy-5H-[1]benzopyrano[4,3-d]pyrimidines:Synthesis and Pharmacological Evaluation
Medicinal Chemistry Diabetic Retinopathy and Atherosclerosis: is there a Link?
Current Diabetes Reviews Diabetes Therapy: Novel Patents Targeting the Glucose-Induced Insulin Secretion
Recent Patents on DNA & Gene Sequences Beyond Rodent Models of Pain: Non-Human Primate Models for Evaluating Novel Analgesic Therapeutics and Elaborating Pain Mechanisms
CNS & Neurological Disorders - Drug Targets Targeting Platelet-Neutrophil Interactions in Giant-Cell Arteritis
Current Pharmaceutical Design SUMOylation in Neurological Diseases
Current Molecular Medicine Minoxidil Use in Dermatology, Side Effects and Recent Patents
Recent Patents on Inflammation & Allergy Drug Discovery Modulation of Fatty Acids Oxidation in Heart Failure by Selective Pharmacological Inhibition of 3-Ketoacyl Coenzyme-A Thiolase
Current Clinical Pharmacology Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile
Current Cancer Drug Targets Vascular Damage in Impaired Glucose Tolerance: An Unappreciated Phenomenon?
Current Pharmaceutical Design Synthetic Methods for the Preparation of Triazepandiones and Review of their Applications
Current Organic Chemistry Controversies in Glaucoma: Current Medical Treatment and Drug Development
Current Pharmaceutical Design Immunomodulation in Inflammatory Neuropathies: Rationale and Safety
Current Drug Safety The Preventive Effect of IL-1beta Antagonist on Diabetic Peripheral Neuropathy
Endocrine, Metabolic & Immune Disorders - Drug Targets Effects of Metabolic Approach in Diabetic Patients with Coronary Artery Disease
Current Pharmaceutical Design SGLT2 Inhibitors in Diabetes Mellitus Treatment
Reviews on Recent Clinical Trials Structure-Activity Relationships of Glutamate Carboxypeptidase II (GCPII) Inhibitors
Current Medicinal Chemistry Receptor for Advanced Glycation End Products (RAGE): A Novel Therapeutic Target for Diabetic Vascular Complication
Current Pharmaceutical Design