【摘 要】
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High throughput screening is the source of chemical starting points for a majority of drug discovery programs in the pharmaceutical industry.In most cases,the resulting hit list from the screening cam
【机 构】
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Biomolecular Structure Novartis Institutes for Biomedical Research USA
【出 处】
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中国上海第七届国际新药发明科技年会
论文部分内容阅读
High throughput screening is the source of chemical starting points for a majority of drug discovery programs in the pharmaceutical industry.In most cases,the resulting hit list from the screening campaign is a combination of "true" inhibitors,which interact in a 1∶1 fashion with the target protein,and compounds that inhibit through a non-desirable mechanism (non-specific binding,protein precipitation,interaction with substrate,assay readout artifacts,etc.).While many long standing biophysical techniques have been used to distinguish "true" inhibitors from false artifacts,traditionally these techniques have been applied to selected compounds at later stages of drug discovery programs.A case study of an atypical kinase will be presented in which an integrated hit finding strategy is used to find desirable chemistry starting points.A flowchart of biophysical techniques is used to assess direct binding of compound to the target protein on the HTS hit list.The result is a list of hits that have all been validated as "true" binders through a direct interaction with the target protein,and elimination of false positives.The integration of fragment based screening,biophysical competition,and structural studies will also be presented as part of the integrated hit finding strategy.The aim of this work is to deliver a list of highly validated inhibitors with additional functional and structural information prior to the start of chemistry efforts with the hope of improving the chemical starting points and shortening the hit to lead optimization phase of a program.
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