Abstract
Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.g. the serine/threonine protein kinases, PknB and PknG, NAD kinase and the NAD synthetase. Here we describe some early efforts in the development of novel signal transduction inhibitory anti-mycobacterial drugs using a multiple target approach, with special emphasis on the kinase inhibitory field. Initially, we are using the Nested Chemical Library™ (NCL) technology and pharmacophore modelling. A hit-finding library, consisting of ∼19000 small molecules with a bias for prototypic kinase inhibitors from our NCL library and commercial sources was virtually screened against these validated target molecules. Protein structures for the virtual screening were taken from the published three dimensional crystal structures of the enzymes. The hits from the virtual screening were subsequently tested in enzymatic assay systems. Potent hits were then tested for biological activity in macrophages, infected with mycobacteria. The final goal of this exercise is not only to identify potent antimycobacterial substances, but also a common pharmacophore for the mycobacterial target PknG in combination with PknB, NAD kinase and/or NAD synthetase. This common pharmacophore still needs to be a unique pharmacophore for the mycobacterial target proteins over human off-targets. Such a pharmacophore might then drive the optimization of a completely new profile of an antibiotic agent with activity against latent mycobacteria and resistance mycobacterial strains.
Keywords: Mycobacterium tuberculosis, PknA, PknB, PknG, NAD kinase, NAD synthetase
Current Medicinal Chemistry
Title: Signalling Inhibitors Against Mycobacterium tuberculosis – Early Days of a New Therapeutic Concept in Tuberculosis
Volume: 15 Issue: 26
Author(s): D. Eros, G. Keri, L. Orfi, B. M. Klebl, Y. Av-Gay, M. Ko, D. Hafenbradl, M. Rizzi, S. Perozzi, S. Garavaglia, N. Breza, C. Szantai-Kis, B. Hegymegi-Barakonyi, J. Marosfalvi, G. Meszaros, Z. Horvath, Z. Greff, J. Pato, P. Banhegyi, G. Nemeth, G. Borbely, R. Kiss, Z. Varga and R. Szekely
Affiliation:
Keywords: Mycobacterium tuberculosis, PknA, PknB, PknG, NAD kinase, NAD synthetase
Abstract: Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.g. the serine/threonine protein kinases, PknB and PknG, NAD kinase and the NAD synthetase. Here we describe some early efforts in the development of novel signal transduction inhibitory anti-mycobacterial drugs using a multiple target approach, with special emphasis on the kinase inhibitory field. Initially, we are using the Nested Chemical Library™ (NCL) technology and pharmacophore modelling. A hit-finding library, consisting of ∼19000 small molecules with a bias for prototypic kinase inhibitors from our NCL library and commercial sources was virtually screened against these validated target molecules. Protein structures for the virtual screening were taken from the published three dimensional crystal structures of the enzymes. The hits from the virtual screening were subsequently tested in enzymatic assay systems. Potent hits were then tested for biological activity in macrophages, infected with mycobacteria. The final goal of this exercise is not only to identify potent antimycobacterial substances, but also a common pharmacophore for the mycobacterial target PknG in combination with PknB, NAD kinase and/or NAD synthetase. This common pharmacophore still needs to be a unique pharmacophore for the mycobacterial target proteins over human off-targets. Such a pharmacophore might then drive the optimization of a completely new profile of an antibiotic agent with activity against latent mycobacteria and resistance mycobacterial strains.
Export Options
About this article
Cite this article as:
Eros D., Keri G., Orfi L., Klebl M. B., Av-Gay Y., Ko M., Hafenbradl D., Rizzi M., Perozzi S., Garavaglia S., Breza N., Szantai-Kis C., Hegymegi-Barakonyi B., Marosfalvi J., Meszaros G., Horvath Z., Greff Z., Pato J., Banhegyi P., Nemeth G., Borbely G., Kiss R., Varga Z. and Szekely R., Signalling Inhibitors Against Mycobacterium tuberculosis – Early Days of a New Therapeutic Concept in Tuberculosis, Current Medicinal Chemistry 2008; 15 (26) . https://dx.doi.org/10.2174/092986708786242886
DOI https://dx.doi.org/10.2174/092986708786242886 |
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
-
Virtual Screening, Docking, Synthesis and Bioactivity Evaluation of Thiazolidinediones as Potential PPARγ Partial Agonists for Preparation of Antidiabetic Agents
Letters in Drug Design & Discovery Biopolymer Catalysed Synthesis of 6-methyl-4-phenylcarbamoyl-1, 2, 3, 4- Tetrahydropyrimidine-2-ones and Evaluation of their Anti-bacterial and Anti-tubercular Activities
Current Bioactive Compounds Is Anticoagulation with Novel Oral Anticoagulants an Effective Treatment for Tuberculosis Patients not Achieving a Therapeutic Range with Vitamin K Antagonists? A Systematic Review
Cardiovascular & Hematological Disorders-Drug Targets Role of CD73 in Disease: Promising Prognostic Indicator and Therapeutic Target
Current Medicinal Chemistry Selection of Targets for Drug Development Against Protozoan Parasites
Current Drug Targets Impact of Diabetes Mellitus on Radiological Presentation of Pulmonary Tuberculosis in Otherwise Non-Immunocompromised Patients: A Systematic Review
Current Medical Imaging Pleural Fluid Analysis for Evaluating Pleural Effusions
Current Respiratory Medicine Reviews Editorial [Hot topic: Structure-Based Virtual Screening (Guest Editor: Walter Filgueira De Azevedo Jr.)]
Current Drug Targets Cationic Antimicrobial Peptides for Tuberculosis: A Mini-Review
Current Protein & Peptide Science Targeting Tuberculosis: A Glimpse of Promising Drug Targets
Mini-Reviews in Medicinal Chemistry In Silico Assessment of Adverse Effects of a Large Set of 6-Fluoroquinolones Obtained from a Study of Tuberculosis Chemotherapy
Current Drug Safety Prophylactic Admission of an In Vitro Reconstructed Complexes of Human Recombinant Heat Shock Proteins and Melanoma Antigenic Peptides Activates Anti-Melanoma Responses in Mice
Current Molecular Medicine Performance of Genotype MTBDRplus in the Detection of Resistance to Rifampicin and Isoniazid Among Clinical Mycobacteria Isolates in Ilorin, Nigeria
Current HIV Research Recent Advances in the Development of Novel Therapeutics Targeting Dendritic Cells
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Subject Index To Volume 13
Current Medicinal Chemistry Synthesis, Reactions and Biological Evaluation of 3-Amino-6- (subs.)thieno[2,3-b]pyridine-2-carbohydrazides
Current Bioactive Compounds Biological Evaluation of Halogenated Thioureas as Cholinesterases Inhibitors Against Alzheimer’s Disease & Molecular Modeling Studies
Letters in Drug Design & Discovery Glycoconjugates of Quinolines: Application in Medicinal Chemistry
Mini-Reviews in Medicinal Chemistry MIF and the Genetic Basis of Macrophage Responsiveness
Current Immunology Reviews (Discontinued) Efficacy, Tolerability and Virological Consequences of Long-Term Use of Unboosted Atazanavir Plus 2 NRTIs in HIV-Infected Patients
Current HIV Research