Abstract
Mycobacterial enoyl acyl carrier protein (ACP) reductase is an attractive target for focused design of novel antitubercular agents. Structural information available on enoyl-ACP reductase in complex with different ligands was used to generate receptor-based pharmacophore model in Discovery Studio (DS). In parallel, pharmacophore models were also generated using ligand-based approach (HypoGen module in DS). Statistically significant models were generated (r2 = 0.85) which were found to be predictive as indicated from internal and external cross-validations. The model was used as a query tool to search Zinc and Maybridge databases to identify lead compounds and predict their activity in silico. Database searching retrieved many potential lead compounds having better estimated IC50 values than the training set compounds. These compounds were then evaluated for their drug-likeliness and pharmacokinetic properties using DS. Few selected compounds were then docked into the crystal structure of enoyl-ACP reductase using Dock 6.5. Most compounds were found to have high score values, which was found to be consistent with the results from pharmacophore mapping. Additionally, molecular docking provided useful insights into the nature of binding of the identified hit molecules. In summary, we show a useful strategy employing ligand- and structure-based approaches (pharmacophore modeling coupled with molecular docking) to identify new enoyl- ACP reductase inhibitors for antimycobacterial chemotherapy.
Keywords: Mycobacterium tuberculosis, enoyl acyl carrier protein reductase, pharmacophore modeling, molecular docking, binding interactions.
Current Pharmaceutical Design
Title:A Rational Approach to Identify Inhibitors of Mycobacterium tuberculosis Enoyl Acyl Carrier Protein Reductase
Volume: 19 Issue: 21
Author(s): Mahesh T Chhabria, Kailash B Parmar and Pathik S Brahmkshatriya
Affiliation:
Keywords: Mycobacterium tuberculosis, enoyl acyl carrier protein reductase, pharmacophore modeling, molecular docking, binding interactions.
Abstract: Mycobacterial enoyl acyl carrier protein (ACP) reductase is an attractive target for focused design of novel antitubercular agents. Structural information available on enoyl-ACP reductase in complex with different ligands was used to generate receptor-based pharmacophore model in Discovery Studio (DS). In parallel, pharmacophore models were also generated using ligand-based approach (HypoGen module in DS). Statistically significant models were generated (r2 = 0.85) which were found to be predictive as indicated from internal and external cross-validations. The model was used as a query tool to search Zinc and Maybridge databases to identify lead compounds and predict their activity in silico. Database searching retrieved many potential lead compounds having better estimated IC50 values than the training set compounds. These compounds were then evaluated for their drug-likeliness and pharmacokinetic properties using DS. Few selected compounds were then docked into the crystal structure of enoyl-ACP reductase using Dock 6.5. Most compounds were found to have high score values, which was found to be consistent with the results from pharmacophore mapping. Additionally, molecular docking provided useful insights into the nature of binding of the identified hit molecules. In summary, we show a useful strategy employing ligand- and structure-based approaches (pharmacophore modeling coupled with molecular docking) to identify new enoyl- ACP reductase inhibitors for antimycobacterial chemotherapy.
Export Options
About this article
Cite this article as:
T Chhabria Mahesh, B Parmar Kailash and S Brahmkshatriya Pathik, A Rational Approach to Identify Inhibitors of Mycobacterium tuberculosis Enoyl Acyl Carrier Protein Reductase, Current Pharmaceutical Design 2013; 19 (21) . https://dx.doi.org/10.2174/1381612811319210012
DOI https://dx.doi.org/10.2174/1381612811319210012 |
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
-
A Glance on the Role of Bacterial Siderophore from the Perspectives of Medical and Biotechnological Approaches
Current Drug Targets Synthesis, In silico Molecular Docking and Pharmacokinetic Studies, In vitro Antimycobacterial and Antimicrobial Studies of New Imidozolones Clubbed with Thiazolidinedione
Current Computer-Aided Drug Design Computational Studies of Molecular Targets Regarding the Adverse Effects of Isoniazid Drug for Tuberculosis
Current Pharmacogenomics and Personalized Medicine Subject Index To Volume 13
Current Medicinal Chemistry Microwave Assisted Synthesis and Antimicrobial Activity Evaluation of New Heterofunctionalized Norfloxacine Derivatives
Letters in Drug Design & Discovery Matrix Metalloproteinases in Respiratory Diseases: From Pathogenesis to Potential Clinical Implications
Current Medicinal Chemistry <I>In silico</I> Studies, Synthesis and Antitubercular Activity of Some Novel Quinoline - Azitidinone Derivatives
Current Computer-Aided Drug Design Melatonin in Bacterial and Viral Infections with Focus on Sepsis: A Review
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Natural Resins and Bioactive Natural Products thereof as Potential Anitimicrobial Agents
Current Pharmaceutical Design Synthesis, Characterization and In Vitro Antiproliferative Effects of Novel 5-Amino Pyrazole Derivatives against Breast Cancer Cell Lines
Recent Patents on Anti-Cancer Drug Discovery Drug Targeting Strategies for Photodynamic Therapy
Anti-Cancer Agents in Medicinal Chemistry The Role of T-Helper Cells in Atherosclerosis
Cardiovascular & Hematological Agents in Medicinal Chemistry 2D Depiction of Biological Interactions and Its Applications in Drug Design
Current Medical Imaging Synthesis and Antibacterial Activity of Mefloquine-Based Analogs Against Sensitive and Resistant Mycobacterium tuberculosis Strains
Current Topics in Medicinal Chemistry Lipid-Specific Immune Responses Against Tuberculosis: From Basic Science to Medical Applications
Current Immunology Reviews (Discontinued) Progress in Nanoparticulate Systems for Peptide, Proteins and Nucleic Acid Drug Delivery
Current Pharmaceutical Biotechnology Structural Bioinformatic Approaches to the Discovery of New Antimycobacterial Drugs
Current Pharmaceutical Design Green Synthesis of N-doped Graphene Nanosheets by Cow Urine
Current Graphene Science (Discontinued) Induced Folding Under Membrane Mimetic and Acidic Conditions Implies Undiscovered Biological Roles of Prokaryotic Ubiquitin-Like Protein Pup
Protein & Peptide Letters Weight Loss in Older Persons: New Therapeutic Approaches
Current Pharmaceutical Design