Efficient Optimization Strategy for Marginal Hits Active Against abl Tyrosine Kinases

Author(s): Sergey E. Tkachenko, Ilya Okun, Konstantin V. Balakin, Charles E. Petersen, Yan A. Ivanenkov, Nikolay P. Savchuk, Andrey A. Ivashchenko.

Journal Name: Current Drug Discovery Technologies

Volume 1 , Issue 3 , 2004

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

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Article Details

VOLUME: 1
ISSUE: 3
Year: 2004
Page: [201 - 210]
Pages: 10
DOI: 10.2174/1570163043335018
Price: $58