Abstract
Background: The tumor pyruvate kinase M2 (PKM2) is involved in the glycolytic pathway of lung cancer and targeting this kinase has been observed to radiosensitize non-small cell lung cancer (NSCLC).
Objective: An integration of in silico virtual screening and in vitro kinase assay was described to discover novel PKM2 inhibitors from a candidate library containing >400,000 commercially available compounds.
Method: The method is a stepwise screening scheme that first used empirical strategies to fast exclude those undruggable compounds in the library and then employed molecular docking and molecular dynamics (MD)-based rescoring to identify few potential hits. Subsequently, the computational findings were substantiated using a standard kinase assay protocol.
Results: Four compounds, i.e. nalidixic acid, indoprofen, hematoxylin and polydatin, were identified to inhibit PKM2 kinase at micromolar level, with IC50 values of 53, 21, 340 and 128 M, respectively.
Conclusion: Structural analysis revealed that hydrogen bonds, salt bridges, - stacking and hydrophobic forces co-confer high stability and strong specificity to PKM2–inhibitor binding.
Keywords: Tumor pyruvate kinase M2, kinase inhibitor, virtual screening, lung cancer.
Medicinal Chemistry
Title:Integrated In Silico-In Vitro Discovery of Lung Cancer-related Tumor Pyruvate Kinase M2 (PKM2) Inhibitors
Volume: 12 Issue: 7
Author(s): Xiangyun Ye, Yinjia Sun, Yunhua Xu, Zhiwei Chen and Shun Lu
Affiliation:
Keywords: Tumor pyruvate kinase M2, kinase inhibitor, virtual screening, lung cancer.
Abstract: Background: The tumor pyruvate kinase M2 (PKM2) is involved in the glycolytic pathway of lung cancer and targeting this kinase has been observed to radiosensitize non-small cell lung cancer (NSCLC).
Objective: An integration of in silico virtual screening and in vitro kinase assay was described to discover novel PKM2 inhibitors from a candidate library containing >400,000 commercially available compounds.
Method: The method is a stepwise screening scheme that first used empirical strategies to fast exclude those undruggable compounds in the library and then employed molecular docking and molecular dynamics (MD)-based rescoring to identify few potential hits. Subsequently, the computational findings were substantiated using a standard kinase assay protocol.
Results: Four compounds, i.e. nalidixic acid, indoprofen, hematoxylin and polydatin, were identified to inhibit PKM2 kinase at micromolar level, with IC50 values of 53, 21, 340 and 128 M, respectively.
Conclusion: Structural analysis revealed that hydrogen bonds, salt bridges, - stacking and hydrophobic forces co-confer high stability and strong specificity to PKM2–inhibitor binding.
Export Options
About this article
Cite this article as:
Ye Xiangyun, Sun Yinjia, Xu Yunhua, Chen Zhiwei and Lu Shun, Integrated In Silico-In Vitro Discovery of Lung Cancer-related Tumor Pyruvate Kinase M2 (PKM2) Inhibitors, Medicinal Chemistry 2016; 12 (7) . https://dx.doi.org/10.2174/1573406412666160307151535
DOI https://dx.doi.org/10.2174/1573406412666160307151535 |
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
-
Roles of Casein Kinase I η and δ in Gastrointestinal Cancers: Potential New Screening Markers and Drug Targets
Current Cancer Therapy Reviews The FDG-PET Revolution of Medical Imaging – Four Decades and Beyond
Current Molecular Imaging (Discontinued) Targeting Signaling Pathways in Chronic Lymphocytic Leukemia
Current Cancer Drug Targets Aptamers as Targeting Delivery Devices or Anti-cancer Drugs for Fighting Tumors
Current Drug Metabolism Therapeutical Approaches of Vasoactive Intestinal Peptide as a Pleiotropic Immunomodulator
Current Pharmaceutical Design Salinomycin Modulates the Expression of mRNAs and miRNAs Related to Stemness in Endometrial Cancer
Current Pharmaceutical Biotechnology Regulatory Roles of the Ubiquitin-Proteasome System in Cardiomyocyte Apoptosis
Current Molecular Medicine Polymorphisms of Human N-Acetyltransferases and Cancer Risk
Current Drug Metabolism Epigenetic Regulation and Promising Therapies in Colorectal Cancer
Current Molecular Pharmacology β -Glucans and their Applications in Cancer Therapy: Focus on human studies
Anti-Cancer Agents in Medicinal Chemistry Severe Hypoglycemia Due to Possible Interaction Between Glibenclamide and Sorafenib in a Patient with Hepatocellular Carcinoma
Current Drug Safety Monitoring Therapy with Gene Expression Profiling Reveals Physiological Differences in Drug Action
Current Pharmaceutical Design Preface [Hot Topic: Marine Natural Products (Guest Editor: Vassilios Roussis)]
Current Medicinal Chemistry Nucleosides with Modified Sugar Ring: Synthesis and Biological Activities
Current Organic Chemistry Role of microRNAs in Hepatic Stellate Cells and Hepatic Fibrosis: An Update
Current Pharmaceutical Design A Focus on Heme Oxygenase-1 (HO-1) Inhibitors
Current Medicinal Chemistry Polyphenols in Disease: from Diet to Supplements
Current Pharmaceutical Biotechnology Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer
Current Pharmaceutical Biotechnology Gene Expression Profiling in Rodent Models for Schizophrenia
Current Neuropharmacology Transactivation of EGFR by G Protein-Coupled Receptor in the Pathophysiology of Intimal Hyperplasia
Current Vascular Pharmacology