Activity cliffs and activity cliff generators based on chemotype-related activity landscapes

Activity cliffs have large impact in drug discovery; therefore, their detection and quantification are of major importance. This work introduces the metric activity cliff enrichment factor and expands the previously reported activity cliff generator concept by adding chemotype information to representations of the activity landscape. To exemplify these concepts, three molecular databases with multiple biological activities were characterized. Compounds in each database were grouped into chemotype classes. Then, pairwise comparisons of structure similarities and activity differences were calculated for each compound and used to construct chemotype-based structure–activity similarity (SAS) maps. Different landscape distributions among four major regions of the SAS maps were observed for different subsets of molecules grouped in chemotypes. Based on this observation, the activity cliff enrichment factor was calculated to numerically detect chemotypes enriched in activity cliffs. Several chemotype classes were detected having major proportion of activity cliffs than the entire database. In addition, some chemotype classes comprising compounds with smooth structure activity relationships (SAR) were detected. Finally, the activity cliff generator concept was applied to compounds grouped in chemotypes to extract valuable SAR information.Graphic abstract

[1]  James G. Nourse,et al.  Reoptimization of MDL Keys for Use in Drug Discovery , 2002, J. Chem. Inf. Comput. Sci..

[2]  John M. Barnard,et al.  Chemical Similarity Searching , 1998, J. Chem. Inf. Comput. Sci..

[3]  Rajarshi Guha,et al.  Structure—Activity Landscape Index: Identifying and Quantifying Activity Cliffs. , 2008 .

[4]  Gerald M. Maggiora,et al.  On Outliers and Activity Cliffs-Why QSAR Often Disappoints , 2006, J. Chem. Inf. Model..

[5]  Ramaswamy Nilakantan,et al.  Topological torsion: a new molecular descriptor for SAR applications. Comparison with other descriptors , 1987, J. Chem. Inf. Comput. Sci..

[6]  José L. Medina-Franco,et al.  Structure–activity relationships of benzimidazole derivatives as antiparasitic agents: Dual activity-difference (DAD) maps , 2011 .

[7]  Jun Xu.  A new approach to finding natural chemical structure classes. , 2002, Journal of medicinal chemistry.

[8]  Vladimir Poroikov,et al.  Chemical Similarity Assessment through Multilevel Neighborhoods of Atoms: Definition and Comparison with the Other Descriptors , 1999, J. Chem. Inf. Comput. Sci..

[9]  Jaime Pérez-Villanueva,et al.  CASE Plots for the Chemotype‐Based Activity and Selectivity Analysis: A CASE Study of Cyclooxygenase Inhibitors , 2012, Chemical biology & drug design.

[10]  D. Moller,et al.  New drug targets for type 2 diabetes and the metabolic syndrome , 2001, Nature.

[11]  Xi Chen,et al.  The Binding Database: data management and interface design , 2002, Bioinform..

[12]  Michael J. Sorich,et al.  Molecular Modeling Approaches for the Prediction of the Nonspecific Binding of Drugs to Hepatic Microsomes. , 2007 .

[13]  J. Bajorath,et al.  SAR index: quantifying the nature of structure-activity relationships. , 2007, Journal of medicinal chemistry.

[14]  J. Bajorath,et al.  Structure-activity relationship anatomy by network-like similarity graphs and local structure-activity relationship indices. , 2008, Journal of medicinal chemistry.

[15]  José L. Medina-Franco,et al.  Scanning Structure-Activity Relationships with Structure-Activity Similarity and Related Maps: From Consensus Activity Cliffs to Selectivity Switches , 2012, J. Chem. Inf. Model..

[16]  Qiong Gu,et al.  Drug discovery inspired by mother nature: seeking natural biochemotypes and the natural assembly rules of the biochemome. , 2013, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[17]  Michael K. Gilson,et al.  Tork: Conformational analysis method for molecules and complexes , 2003, J. Comput. Chem..

[18]  Dongqing Wei,et al.  Chemomics and drug innovation , 2012, Science China Chemistry.

[19]  P. Jaccard,et al.  Etude comparative de la distribution florale dans une portion des Alpes et des Jura , 1901 .

[20]  Mathias Wawer,et al.  Navigating structure-activity landscapes. , 2009, Drug discovery today.

[21]  José L. Medina-Franco,et al.  Consensus Models of Activity Landscapes with Multiple Chemical, Conformer, and Property Representations , 2011, J. Chem. Inf. Model..

[22]  R. Brekken,et al.  Apricoxib, a Novel Inhibitor of COX-2, Markedly Improves Standard Therapy Response in Molecularly Defined Models of Pancreatic Cancer , 2012, Clinical Cancer Research.

[23]  Jaime Pérez-Villanueva,et al.  Towards a systematic characterization of the antiprotozoal activity landscape of benzimidazole derivatives. , 2010, Bioorganic & medicinal chemistry.

[24]  X Chen,et al.  The binding database: overview and user's guide. , 2001, Biopolymers.

[25]  Claus Schneider,et al.  Cyclooxygenases and lipoxygenases in cancer , 2011, Cancer and Metastasis Reviews.

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

[27]  Jaime Pérez-Villanueva,et al.  Activity landscape modeling of PPAR ligands with dual-activity difference maps. , 2012, Bioorganic & medicinal chemistry.

[28]  Jürgen Bajorath,et al.  Extending the Activity Cliff Concept: Structural Categorization of Activity Cliffs and Systematic Identification of Different Types of Cliffs in the ChEMBL Database , 2012, J. Chem. Inf. Model..

[29]  Jürgen Bajorath,et al.  Large-Scale Assessment of Activity Landscape Feature Probabilities of Bioactive Compounds , 2014, J. Chem. Inf. Model..

[30]  R. Venkataraghavan,et al.  Atom pairs as molecular features in structure-activity studies: definition and applications , 1985, J. Chem. Inf. Comput. Sci..

[31]  Gerald M. Maggiora,et al.  Hierarchical Strategy for Identifying Active Chemotype Classes in Compound Databases , 2006, Chemical biology & drug design.

[32]  José L. Medina-Franco,et al.  Characterization of Activity Landscapes Using 2D and 3D Similarity Methods: Consensus Activity Cliffs , 2009, J. Chem. Inf. Model..

[33]  Austin B. Yongye,et al.  Multitarget Structure-Activity Relationships Characterized by Activity-Difference Maps and Consensus Similarity Measure , 2011, J. Chem. Inf. Model..

[34]  Peter Willett,et al.  Combination Rules for Group Fusion in Similarity‐Based Virtual Screening , 2010, Molecular informatics.

[35]  J. A. Grant,et al.  A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction. , 2005, Journal of medicinal chemistry.

[36]  Xin Wen,et al.  BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities , 2006, Nucleic Acids Res..

[37]  R. Gainetdinov,et al.  Plasma membrane monoamine transporters: structure, regulation and function , 2003, Nature Reviews Neuroscience.

[38]  J. Bajorath,et al.  Comparison of two- and three-dimensional activity landscape representations for different compound data sets , 2011 .

[39]  Yong-Jin Xu,et al.  Algorithm for Naming Molecular Equivalence Classes Represented by Labeled Pseudographs. , 2001 .

[40]  Maykel Cruz-Monteagudo,et al.  Activity cliffs in drug discovery: Dr Jekyll or Mr Hyde? , 2014, Drug discovery today.

[41]  Oscar Méndez-Lucio,et al.  Activity landscape analysis, CoMFA and CoMSIA studies of pyrazole CB1 antagonists , 2012, Medicinal Chemistry Research.

[42]  Manish Sud,et al.  MayaChemTools: An Open Source Package for Computational Drug Discovery , 2016, J. Chem. Inf. Model..

[43]  S. Ganti,et al.  PPAR dual agonists: are they opening Pandora's Box? , 2007, Pharmacological research.

[44]  Lemont B. Kier,et al.  Electrotopological State Indices for Atom Types: A Novel Combination of Electronic, Topological, and Valence State Information , 1995, J. Chem. Inf. Comput. Sci..

[45]  Jürgen Bajorath,et al.  Exploring activity cliffs in medicinal chemistry. , 2012, Journal of medicinal chemistry.

[46]  S. Ramamoorthy,et al.  Regulation of monoamine transporters: Influence of psychostimulants and therapeutic antidepressants , 2005, The AAPS Journal.

[47]  Jaime Pérez-Villanueva,et al.  Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of some benzimidazole derivatives with trichomonicidal activity. , 2011, European journal of medicinal chemistry.

[48]  Oscar Méndez-Lucio,et al.  Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps , 2012, Molecular informatics.

[49]  Benjamin Parent,et al.  Fuzzy Tricentric Pharmacophore Fingerprints, 1. Topological Fuzzy Pharmacophore Triplets and Adapted Molecular Similarity Scoring Schemes , 2006, J. Chem. Inf. Model..

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

[51]  Anne Mai Wassermann,et al.  Design of Multitarget Activity Landscapes That Capture Hierarchical Activity Cliff Distributions , 2011, J. Chem. Inf. Model..