The Impact of Tautomer Forms on Pharmacophore-Based Virtual Screening

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• 作者：Frank Oellien ; Jö ; rg Cramer ; Carsten Beyer ; Wolf-Dietrich Ihlenfeldt ; Paul M. Selzer
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2006
• 出版时间：November 2006
• 年：2006
• 卷：46
• 期：6
• 页码：2342 - 2354
• 全文大小：756K
• 年卷期：v.46,no.6(November 2006)
• ISSN：1549-960X

文摘

In the field of in silico screening, many applications do not automatically consider possible tautomericstates of molecules. However, the detection of new compound candidates might rely on correct structuraldescription, which is important for the perfect fit toward the biologically relevant interactions. In this paper,we present a new exhaustive tautomer enumeration approach implemented by means of the CACTVS softwarepackage. The approach contains a set of 21 predefined SMIRKS-based transforms and a powerfultransformation engine that is capable of generating most tautomers described comprehensively in the literatureor found in databases in the field of medicinal chemistry. User-defined tautomer rules applied to specificstructural databases or scientific issues can be implemented easily and used instead of the predefined rules.In addition, we describe the impact of tautomer-enriched databases on pharmacophore screening approachesfor human matrix metalloproteinase 8 as an example of a protein-based pharmacophore screening scenarioand for human cyclin-dependent kinases as an example of a ligand-based pharmacophore screening approach.In both test cases, as a preprocessing step, we have used our new tautomer enumerator tool for the tautomerenrichment of the screening data sets and have used it as a postprocessing step to remove tautomeric duplicatesfrom the results. We could demonstrate that the tautomer-enriched screening data sets show significantadvantages compared to their non-enhanced counterparts. The discrimination between hits and nonhits wassignificantly better in the case of tautomer-enriched databases. Moreover, it has been proved that tautomer-enhanced databases will lead to a higher number of potential hits.