Abstract
Background: Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpression of hSIRT1 leads to cancer, inhibiting its HDAC function may be a better strategy for the treatment of cancer. Till now, only a few reported inhibitor compounds have reached the stage of animal studies; hence, identifying high efficacy inhibitors of hSIRT1 is essential.
Objective: The main objective of the study is to obtain a new class of inhibitor compounds of hSIRT1 by the rational structure-based method.
Methodology: We performed virtual screening using AutoDock Vina for the HDAC domain of hSIRT1 against the Drug- Bank library containing 1,716 compounds. The recently determined crystal structure of the HDAC domain of hSIRT1 (PDB Id: 4KXQ) was used for docking studies. Subsequently, we performed molecular dynamics simulations and an invitro deacetylase assay for selected compounds.
Results: Virtual screening studies yielded seven compounds from two chemical classes, namely diphenyl and oxycoumarin derivatives. Molecular dynamic simulations confirmed that the predicted seven compounds bind well to their respective complex structures. Moreover, four commercially available drugs containing the predicted compounds showed significant inhibition of hSIRT1 deacetylase activity in comparison to the known hSIRT1 inhibitor (sirtinol).
Conclusion: Our results indicate that the compounds of the diphenyl and oxycoumarin series may serve as useful scaffolds in the development of new chemical libraries of hSIRT1 inhibitory activity.
Keywords: Sirtuins, human SIRT1, virtual screening, DrugBank, inhibitors, diphenyl and oxycoumarin derivatives, molecular dynamics, HDAC assay.
Medicinal Chemistry
Title:Identification of New Inhibitors for Human SIRT1: An in-silico Approach
Volume: 12 Issue: 4
Author(s): Balasundaram Padmanabhan, Manjula Ramu, Shruti Mathur, Sruthi Unni and Saravanamuthu Thiyagarajan
Affiliation:
Keywords: Sirtuins, human SIRT1, virtual screening, DrugBank, inhibitors, diphenyl and oxycoumarin derivatives, molecular dynamics, HDAC assay.
Abstract: Background: Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpression of hSIRT1 leads to cancer, inhibiting its HDAC function may be a better strategy for the treatment of cancer. Till now, only a few reported inhibitor compounds have reached the stage of animal studies; hence, identifying high efficacy inhibitors of hSIRT1 is essential.
Objective: The main objective of the study is to obtain a new class of inhibitor compounds of hSIRT1 by the rational structure-based method.
Methodology: We performed virtual screening using AutoDock Vina for the HDAC domain of hSIRT1 against the Drug- Bank library containing 1,716 compounds. The recently determined crystal structure of the HDAC domain of hSIRT1 (PDB Id: 4KXQ) was used for docking studies. Subsequently, we performed molecular dynamics simulations and an invitro deacetylase assay for selected compounds.
Results: Virtual screening studies yielded seven compounds from two chemical classes, namely diphenyl and oxycoumarin derivatives. Molecular dynamic simulations confirmed that the predicted seven compounds bind well to their respective complex structures. Moreover, four commercially available drugs containing the predicted compounds showed significant inhibition of hSIRT1 deacetylase activity in comparison to the known hSIRT1 inhibitor (sirtinol).
Conclusion: Our results indicate that the compounds of the diphenyl and oxycoumarin series may serve as useful scaffolds in the development of new chemical libraries of hSIRT1 inhibitory activity.
Export Options
About this article
Cite this article as:
Padmanabhan Balasundaram, Ramu Manjula, Mathur Shruti, Unni Sruthi and Thiyagarajan Saravanamuthu, Identification of New Inhibitors for Human SIRT1: An in-silico Approach, Medicinal Chemistry 2016; 12 (4) . https://dx.doi.org/10.2174/1573406412666160107111612
DOI https://dx.doi.org/10.2174/1573406412666160107111612 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...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
Related Articles
-
Nongenomic Actions of Thyroid Hormones: From Basic Research to Clinical Applications. An Update
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Chemotherapy and Targeted Agents for Elderly Women with Advanced Breast Cancer
Recent Patents on Anti-Cancer Drug Discovery Inhibiting Breast Cancer Progression by Exploiting TGFβ Signaling
Current Drug Targets Current Role of Proteomics in Pancreatic Cancer Biomarkers Research
Current Proteomics Role of Rap2 and its Downstream Effectors in Tumorigenesis
Anti-Cancer Agents in Medicinal Chemistry Recent Advancements for the Management of Pancreatic Cancer: Current Insights
Current Cancer Therapy Reviews Diagnostic Performance of Magnetic Resonance Cholangiopancreatography (MRCP) for Biliopancreatic Cancer
Current Medical Imaging Inhibition of Hedgehog/Gli Signaling by Botanicals: A Review of Compounds with Potential Hedgehog Pathway Inhibitory Activities
Current Cancer Drug Targets Circulating Biochemical Markers of Brain Damage in Infants Complicated by Ischemia Reperfusion Injury
Cardiovascular & Hematological Agents in Medicinal Chemistry Understanding Cancer Drug Resistance by Developing and Studying Resistant Cell Line Models
Current Cancer Drug Targets Commentary on “Non-Steroidal Anti-inflammatory Drugs Loaded Liposomes for Topical Treatment of Inflammatory and Degenerative Conditions” by Carla Matos, FP-ENAS-UFP Energy, Environment and Health Research Unit/CEBIMED-Centro de Estudos em Biomedicina, Fernando Pessoa University, Porto, Portugal Challenges and Prospects of Topical Treatment of Inflammatory and Degenerative Conditions: A Vesicular Approach
Current Medicinal Chemistry Bleomycin and its Role in Inducing Apoptosis and Senescence in Lung Cells - Modulating Effects of Caveolin-1
Current Cancer Drug Targets Triggering PIK3CA Mutations in PI3K/Akt/mTOR Axis: Exploration of Newer Inhibitors and Rational Preventive Strategies
Current Pharmaceutical Design Screening and Identification of Differentially Expressed Genes Between Diabetic Nephropathy Glomerular and Normal Glomerular via Bioinformatics Technology
Combinatorial Chemistry & High Throughput Screening Current State of the Art of New Tubulin Inhibitors in the Clinic
Current Clinical Pharmacology Cancer Stem Cells and their Management in Cancer Therapy
Recent Patents on Anti-Cancer Drug Discovery HIV-1 Vectors: Fulfillment of Expectations, Further Advancements, and Still A Way To Go
Current HIV Research Oncogene Expression Modulation in Cancer Cell Lines by DNA G-Quadruplex-Interactive Small Molecules
Current Medicinal Chemistry A Proteomics Study of the Subacute Toxicity of Rat Brain after Long- Term Exposure of <i>Gelsemium elegans</i>
Current Molecular Pharmacology Novel Agents Targeting Crucial Signalling Pathways in Head and Neck Squamous Cell Carcinoma, HNSCC - Preclinical Development and Data from Clinical Trials
Current Proteomics