Exploring activity cliffs in medicinal chemistry.

No. 72, Division of Chemical Information. (15) Wassermann, A. M. ; Dimova, D. ; Bajorath, J. Comprehensive Analysis of Singleand Multi-Target Activity Cliffs Formed by Currently Available Bioactive Compounds. Chem. Biol. Drug Des. 2011, 78, 224−228. (16) Medina-Franco, J. L. ; Martínez-Mayorga, K. ; Bender, A. ; Marín, R. M. ; Giulianotti, M. A. ; Pinilla, C. ; Houghten, R. A. Characterization of Activity Landscapes using 2D and 3D Similarity Methods: Consensus Activity Cliffs. J. Chem. Inf. Model. 2009, 49, 477−491. (17) Yongye, A. B. ; Byler, K. ; Santos, R. ; Martínez-Mayorga, K. ; Maggiora, G. M. ; Medina-Franco, J. L. Consensus Models of Activity Landscapes with Multiple Chemical, Conformer, and Property Representations. J. Chem. Inf. Model. 2011, 51, 2427−2439. (18) Rogers, D. ; Hahn, M. Extended-Connectivity Fingerprints. J. Chem. Inf. Model. 2010, 50, 742−754. (19) MACCS Structural Keys; Symyx Software: San Ramon, CA, 2005. (20) Lajiness, M. Exploring and Exploiting the Potential of Structure−Activity Cliffs. Proceedings of the 240th National Meeting of the American Chemical Society, Boston, MA, August 22−26, 2010; American Chemical Society: Washington, DC, 2010; Abstract No. 61, Division of Chemical Information. (21) Stumpfe, D. ; Bajorath, J. Assessing the Confidence Level of Public Domain Compound Activity Data and the Impact of Alternative Potency Measurements on SAR Analysis. J. Chem. Inf. Model. 2011, 51, 3131−3137. Journal of Medicinal Chemistry Perspective dx.doi. org/10.1021/jm201706b | J. Med. Chem. 2012, 55, 2932−2942 2941 (22) Liu, T. ; Lin, Y. ; Wen, X. ; Jorissen, R. N. ; Gilson, M. K. BindingDB: a Web-Accessible Database of Experimentally Determined Protein−Ligand Binding Affinities. Nucleic Acids Res. 2007, 35, D198− D201. (23) Agrafiotis, D. K. ; Wiener, J. J. M. ; Skalkin, A. ; Kolpak, J. Single R-Group Polymorphisms (SRPs) and R-Cliffs: An Intuitive Framework for Analyzing and Visualizing Activity Cliffs in a Single Analog Series. J. Chem. Inf. Model. 2011, 51, 1122−1132. (24) Peltason, L. ; Hu, Y. ; Bajorath, J. From Structure−Activity to Structure−Selectivity Relationships: Quantitative Assessment, Selectivity Cliffs, and Key Compounds. ChemMedChem 2009, 4, 1864− 1873. (25) Dimova, D. ; Wawer, M. ; Wassermann, A. M. ; Bajorath, J. Design of Multi-Target Activity Landscapes That Capture Hierarchical Activity Cliff Distributions. J. Chem. Inf. Model. 2011, 51, 256−288. (26) Iyer, P.; Stumpfe, D. ; Bajorath, J. Molecular Mechanism-Based Network-like Similarity Graphs Reveal Relationships between Different Types of Receptor Ligands and Structural Changes That Determine Agonistic, Inverse-Agonistic, and Antagonistic Effects. J. Chem. Inf. Model. 2011, 51, 1281−1286. (27) Sisay, M. T. ; Peltason, L. ; Bajorath, J. Structural Interpretation of Activity Cliffs Revealed by Systematic Analysis of Structure− Activity Relationships in Analog Series. J. Chem. Inf. Model. 2009, 49, 2179−2189. (28) Seebeck, B. ; Wagener, M. ; Rarey, M. From Activity Cliffs to Target-Specific Scoring Models and Pharmacophore Hypotheses. ChemMedChem 2011, 6, 1630−1639. (29) Gaulton, A. ; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M. ; Hersey, A. ; Light, Y. ; McGlinchey, S. ; Michalovich, D. ; Al-Lazikani, B. ; Overington, J. P. ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery. Nucleic Acids Res. 2012, 40, D1100−D1107. (30) Kenny, P. W. ; Sadowski, J. Structure Modification in Chemical Databases. In Chemoinformatics in Drug Discovery; Oprea, T. I. , Ed.; Wiley-VCH: Weinheim, Germany, 2005; pp 271−285. (31) Wassermann, A. M. ; Bajorath, J. Chemical Substitutions That Introduce Activity Cliffs across Different Compound Classes and Biological Targets. J. Chem. Inf. Model. 2010, 50, 1248−1256. (32) Bemis, G. W. ; Murcko, M. A. The Properties of Known Drugs. 1. Molecular Frameworks. J. Med. Chem. 1996, 39, 2887−2893. (33) Hu, Y. ; Bajorath, J. Molecular Scaffolds with High Propensity to Form Multi-Target Activity Cliffs. J. Chem. Inf. Model. 2010, 50, 500−510. (34) Vogt, M. ; Huang, Y. ; Bajorath, J. From Activity Cliffs to Activity Ridges: Informative Data Structures for SAR Analysis. J. Chem. Inf. Model. 2011, 51, 1848−1856. (35) Xu, Y. -J.; Johnson, M. Algorithm for Naming Molecular Equivalence Classes Represented by Labeled Pseudographs. J. Chem. Inf. Comput. Sci. 2001, 41, 181−185. (36) Wawer, M. ; Bajorath, J. Local Structural Changes, Global Data Views: Graphical Substructure−Activity Relationship Trailing. J. Med. Chem. 2011, 54, 2944−2951. (37) Lounkine, E. ; Wawer, M. ; Wassermann, A. M. ; Bajorath, J. SARANEA: A Freely Available Program To Mine Structure−Activity and Structure−Selectivity Relationship Information in Compound Data Sets. J. Chem. Inf. Model. 2010, 50, 68−78. (38) Namasivayam, V. ; Iyer, P.; Bajorath, J. Exploring SAR Continuity in the Vicinity of Activity Cliffs. Chem. Biol. Drug Des. 2012, 79, 22−29. (39) Hopkins, A. L. Network Pharmacology: The Next Paradigm in Drug Discovery. Nat. Chem. Biol. 2008, 4, 682−690. (40) Jacoby, E. ; Mozzarelli, A. Chemogenomic Strategies To Expand the Bioactive Chemical Space. Curr. Med. Chem. 2009, 16, 4374−4381. Journal of Medicinal Chemistry Perspective dx.doi. org/10.1021/jm201706b | J. Med. Chem. 2012, 55, 2932−2942 2942