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
-
The Impact of Bariatric Surgery in Patients with Type-2 Diabetes Mellitus
Current Diabetes Reviews Immune Disturbances in Chronic Pain: Cause, Consequence or Both?
Current Immunology Reviews (Discontinued) Aldose Reductase, Still a Compelling Target for Diabetic Neuropathy
Current Drug Targets Changes of Drug Metabolizing Enzymes in the Liver of Male Sheep Exposed to either Cypermethrin or Dimethoate
Drug Metabolism Letters Protein Kinases and their Modulation in the Central Nervous System
Current Medicinal Chemistry - Central Nervous System Agents Pathogens and Chronic or Long-Term Neurologic Disorders
Cardiovascular & Hematological Disorders-Drug Targets Biochemistry and Neurobiology of Prosaposin: A Potential Therapeutic Neuro-Effector
Central Nervous System Agents in Medicinal Chemistry Hyperglycemia-induced Oxidative Stress and its Role in Diabetes Mellitus Related Cardiovascular Diseases
Current Pharmaceutical Design Circulating Nucleic Acids in Plasma and Serum: Roles in Diagnosis and Prognosis in Diabetes and Cancer
Infectious Disorders - Drug Targets Heme Oxygenase -1 Gene Therapy: Recent Advances and Therapeutic Applications
Current Gene Therapy Recent Advances in Management of Diabetic Macular Edema
Current Diabetes Reviews Possible Consequences of Blocking Transient Receptor Potential Vanilloid 1
Current Pharmaceutical Biotechnology Commentary Research Highlights (Purines, Pores and Pain: Is it in Our Genes?)
CNS & Neurological Disorders - Drug Targets Modulation of Cardiac Metabolism During Myocardial Ischemia
Current Pharmaceutical Design The Oxido-reductase Activity of the Apoptosis Inducing Factor: A Promising Pharmacological Tool?
Current Pharmaceutical Design Potential Therapeutic Targets for Neurodegenerative Diseases: Lessons Learned from Calorie Restriction
Current Drug Targets Can Modulating Inflammatory Response be a Good Strategy to Treat Neuropathic Pain?
Current Pharmaceutical Design Gene Expression Analysis Approach to Establish Possible Links Between Parkinson's Disease, Cancer and Cardiovascular Diseases
CNS & Neurological Disorders - Drug Targets Type 2 Diabetes Mellitus Related to Decreased Peripheral and Respiratory Muscle Strength in Sarcopenic Thai Elderly
Current Aging Science Impact of Active Antihyperglycemic Components as Herbal Therapy for Preventive Health Care Management of Diabetes
Current Molecular Medicine