Abstract
Primary high-throughput screening of commercially available small molecules collections often results in hit compounds with unfavorable ADME / Tox properties and low IP potential. These issues are addressed empirically at follow-up lead development and optimization stages. In this work, we describe a rational approach to the optimization of hit compounds discovered during screening of a kinase focused library against abl tyrosine kinase. The optimization strategy involved application of modern chemoinformatics techniques, such as automatic bioisosteric transformation of the initial hits, efficient solution-phase combinatorial synthesis, and advanced methods of knowledge-based libraries design.
Keywords: high-throughput screening, combinatorial synthesis, virtual screening, tyrosine kinase inhibitors, hit optimization, bioisosteric approach, quantitative structure-activity relationship, support vector machines
Current Drug Discovery Technologies
Title: Efficient Optimization Strategy for Marginal Hits Active Against abl Tyrosine Kinases
Volume: 1 Issue: 3
Author(s): Sergey E. Tkachenko, Ilya Okun, Konstantin V. Balakin, Charles E. Petersen, Yan A. Ivanenkov, Nikolay P. Savchuk and Andrey A. Ivashchenko
Affiliation:
Keywords: high-throughput screening, combinatorial synthesis, virtual screening, tyrosine kinase inhibitors, hit optimization, bioisosteric approach, quantitative structure-activity relationship, support vector machines
Abstract: Primary high-throughput screening of commercially available small molecules collections often results in hit compounds with unfavorable ADME / Tox properties and low IP potential. These issues are addressed empirically at follow-up lead development and optimization stages. In this work, we describe a rational approach to the optimization of hit compounds discovered during screening of a kinase focused library against abl tyrosine kinase. The optimization strategy involved application of modern chemoinformatics techniques, such as automatic bioisosteric transformation of the initial hits, efficient solution-phase combinatorial synthesis, and advanced methods of knowledge-based libraries design.
Export Options
About this article
Cite this article as:
Tkachenko E. Sergey, Okun Ilya, Balakin V. Konstantin, Petersen E. Charles, Ivanenkov A. Yan, Savchuk P. Nikolay and Ivashchenko A. Andrey, Efficient Optimization Strategy for Marginal Hits Active Against abl Tyrosine Kinases, Current Drug Discovery Technologies 2004; 1 (3) . https://dx.doi.org/10.2174/1570163043335018
DOI https://dx.doi.org/10.2174/1570163043335018 |
Print ISSN 1570-1638 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6220 |
- 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
-
Preparation and physicochemical characterization of inclusion complexes derived from phytosterols and β-cyclodextrin
Letters in Organic Chemistry On Various Metrics Used for Validation of Predictive QSAR Models with Applications in Virtual Screening and Focused Library Design
Combinatorial Chemistry & High Throughput Screening Polyisoprenylation Potentiates the Inhibition of Polyisoprenylated Methylated Protein Methyl Esterase and the Cell Degenerative Effects of Sulfonyl Fluorides
Current Cancer Drug Targets Myeloperoxidase as a Target for the Treatment of Inflammatory Syndromes: Mechanisms and Structure Activity Relationships of Inhibitors
Current Medicinal Chemistry Bioaccessibility of Bioactive Compounds and Prebiotic Properties of Fruit and Vegetable By-products - A Mini Review
Current Bioactive Compounds Multiple Activities in Lantibiotics - Models for the Design of Novel Antibiotics?
Current Pharmaceutical Design Transient Expression of Chicken Antimicrobial Peptides by Mouse Mammary Carcinoma Cells C127
Protein & Peptide Letters Comparison of Luminescence ADP Production Assay and Radiometric Scintillation Proximity Assay for Cdc7 Kinase
Combinatorial Chemistry & High Throughput Screening A New and Convenient Synthesis of the Boceprevir P1 Fragment, β-amino-α-Hydroxy Amide
Letters in Organic Chemistry Preparation and Characterization of Highly Fluorescent TGA-CdTe Quantum Dot-Hyamine 1622 Additive Composite
Micro and Nanosystems Aldo-Keto Reductase Family 1 Member B1 Inhibitors: Old Drugs with New Perspectives
Recent Patents on Anti-Cancer Drug Discovery Synthesis and Biological Evaluation of Sulfonilamidothienopyrimidinone Derivatives as Novel Anti-inflammatory Agents
Medicinal Chemistry Bioactivities of Iridoids
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Drug Metabolism and Pharmacokinetics of Dammarane Triterpenoids
Current Drug Metabolism Caffeine and Suicide: A Systematic Review
CNS & Neurological Disorders - Drug Targets Centrality Measures in Biological Networks
Current Bioinformatics Thalidomide Metabolism and Hydrolysis: Mechanisms and Implications
Current Drug Metabolism History and Therapeutic Use of MAO-A Inhibitors: A Historical Perspective of MAO-A Inhibitors As Antidepressant Drug
Current Topics in Medicinal Chemistry Approaches to Quantification of RNA Targets by PCR Based Techniques
Current Genomics Effective Preparation, Characterization and In Situ Surface Coating of Superparamagnetic Fe3O4 Nanoparticles with Polyethyleneimine Through Cathodic Electrochemical Deposition (CED)
Current Nanoscience