Effectiveness of 2D fingerprints for scaffold hopping.

BACKGROUND It has been suggested that similarity searching using 2D fingerprints may not be suitable for scaffold hopping. METHODS This article reports a detailed evaluation of the effectiveness of six common types of 2D fingerprints when they are used for scaffold-hopping similarity searches of the Molecular Design Limited Drug Data Report database, World of Molecular Bioactivity database and Maximum Unbiased Validation database. RESULTS The results demonstrate that 2D fingerprints can be used for scaffold hopping, with novel scaffolds being identified in nearly every search that was carried out. The degree of enrichment depends on the structural diversity of the actives that are being sought, with the greatest enrichments often being obtained using the extended connectivity fingerprint encoding a circular substructure of diameter four bonds (ECFP4) fingerprint. CONCLUSION 2D fingerprints provide a simple and computationally efficient way of identifying novel chemotypes in lead-discovery programs.

[1]  Ajay N. Jain,et al.  Effects of inductive bias on computational evaluations of ligand-based modeling and on drug discovery , 2008, J. Comput. Aided Mol. Des..

[2]  J. Gasteiger,et al.  Chemoinformatics: A Textbook , 2003 .

[3]  David Rogers,et al.  Extended-Connectivity Fingerprints , 2010, J. Chem. Inf. Model..

[4]  Robert P Sheridan,et al.  Chemical similarity searches: when is complexity justified? , 2007, Expert opinion on drug discovery.

[5]  Peter Willett,et al.  Similarity methods in chemoinformatics , 2009, Annu. Rev. Inf. Sci. Technol..

[6]  Sebastian G. Rohrer,et al.  Maximum Unbiased Validation (MUV) Data Sets for Virtual Screening Based on PubChem Bioactivity Data , 2009, J. Chem. Inf. Model..

[7]  Jérôme Hert,et al.  Turbo similarity searching: Effect of fingerprint and dataset on virtual‐screening performance , 2009, Stat. Anal. Data Min..

[8]  Yvonne C. Martin,et al.  Application of Belief Theory to Similarity Data Fusion for Use in Analog Searching and Lead Hopping , 2008, J. Chem. Inf. Model..

[9]  Robert C. Glen,et al.  Similarity Metrics and Descriptor Spaces – Which Combinations to Choose? , 2006 .

[10]  Gisbert Schneider,et al.  Scaffold‐Hopping: How Far Can You Jump? , 2006 .

[11]  Peter Willett,et al.  Enhancing the Effectiveness of Ligand‐Based Virtual Screening Using Data Fusion , 2006 .

[12]  G. Schneider,et al.  Scaffold‐Hopping Potential of Ligand‐Based Similarity Concepts , 2006, ChemMedChem.

[13]  Yong-Jin Xu,et al.  Using Molecular Equivalence Numbers to Visually Explore Structural Features that Distinguish Chemical Libraries. , 2002 .

[14]  Hongyu Zhao,et al.  Scaffold selection and scaffold hopping in lead generation: a medicinal chemistry perspective. , 2007, Drug discovery today.

[15]  M. Stahl,et al.  Scaffold hopping. , 2004, Drug discovery today. Technologies.

[16]  J. Bajorath,et al.  Scaffold hopping using two-dimensional fingerprints: true potential, black magic, or a hopeless endeavor? Guidelines for virtual screening. , 2010, Journal of medicinal chemistry.

[17]  Tudor I. Oprea,et al.  Optimization of CAMD techniques 3. Virtual screening enrichment studies: a help or hindrance in tool selection? , 2008, J. Comput. Aided Mol. Des..

[18]  P Willett,et al.  Grouping of coefficients for the calculation of inter-molecular similarity and dissimilarity using 2D fragment bit-strings. , 2002, Combinatorial chemistry & high throughput screening.

[19]  Y. Martin,et al.  Beyond QSAR: Lead Hopping to Different Structures , 2009 .

[20]  S. Siegel,et al.  Nonparametric Statistics for the Behavioral Sciences , 2022, The SAGE Encyclopedia of Research Design.

[21]  Lisa Peltason,et al.  Molecular Similarity Analysis in Virtual Screening , 2009 .

[22]  Peter Willett,et al.  Analysis and use of fragment-occurrence data in similarity-based virtual screening , 2009, J. Comput. Aided Mol. Des..

[23]  P. Willett,et al.  Comparison of topological descriptors for similarity-based virtual screening using multiple bioactive reference structures. , 2004, Organic & biomolecular chemistry.

[24]  Nathan Brown,et al.  On scaffolds and hopping in medicinal chemistry. , 2006, Mini reviews in medicinal chemistry.

[25]  Peter Willett,et al.  Similarity-based virtual screening using 2D fingerprints. , 2006, Drug discovery today.

[26]  Andrew R. Leach,et al.  An Introduction to Chemoinformatics , 2003 .

[27]  Woody Sherman,et al.  Analysis and comparison of 2D fingerprints: insights into database screening performance using eight fingerprint methods , 2010, J. Cheminformatics.

[28]  Woody Sherman,et al.  Large-Scale Systematic Analysis of 2D Fingerprint Methods and Parameters to Improve Virtual Screening Enrichments , 2010, J. Chem. Inf. Model..

[29]  G. Bemis,et al.  The properties of known drugs. 1. Molecular frameworks. , 1996, Journal of medicinal chemistry.