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J Med Chem. 2011 Oct 13;54(19):6771-85. doi: 10.1021/jm200666a. Epub 2011 Sep 14.

Chemical structural novelty: on-targets and off-targets.

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University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94158, United States.


Drug structures may be quantitatively compared based on 2D topological structural considerations and based on 3D characteristics directly related to binding. A framework for combining multiple similarity computations is presented along with its systematic application to 358 drugs with overlapping pharmacology. Given a new molecule along with a set of molecules sharing some biological effect, a single score based on comparison to the known set is produced, reflecting either 2D similarity, 3D similarity, or their combination. For prediction of primary targets, the benefit of 3D over 2D was relatively small, but for prediction of off-targets, the added benefit was large. In addition to assessing prediction, the relationship between chemical similarity and pharmacological novelty was studied. Drug pairs that shared high 3D similarity but low 2D similarity (i.e., a novel scaffold) were shown to be much more likely to exhibit pharmacologically relevant differences in terms of specific protein target modulation.

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