title: Analyzing multitarget activity landscapes using protein-ligand interaction fingerprints: interaction cliffs.
abstract: Activity landscape modeling is mostly a descriptive technique that allows rationalizing continuous and discontinuous SARs. Nevertheless, the interpretation of some landscape features, especially of activity cliffs, is not straightforward. As the nature of activity cliffs depends on the ligand and the target, information regarding both should be included in the analysis. A specific way to include this information is using protein-ligand interaction fingerprints (IFPs). In this paper we report the activity landscape modeling of 507 ligand-kinase complexes (from the KLIFS database) including IFP, which facilitates the analysis and interpretation of activity cliffs. Here we introduce the structure-activity-interaction similarity (SAIS) maps that incorporate information on ligand-target contact similarity. We also introduce the concept of interaction cliffs defined as ligand-target complexes with high structural and interaction similarity but have a large potency difference of the ligands. Moreover, the information retrieved regarding the specific interaction allowed the identification of activity cliff hot spots, which help to rationalize activity cliffs from the target point of view. In general, the information provided by IFPs provides a structure-based understanding of some activity landscape features. This paper shows examples of analyses that can be carried out when IFPs are added to the activity landscape model.
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Oscar
authors.initials: O
authors.lastname: Méndez-Lucio
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kooistra
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
mesh_terms: D000465:Algorithms; D055808:Drug Discovery / Q000379:methods; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D010449:Peptide Mapping / Q000379:methods*; D010770:Phosphotransferases / Q000737:chemistry; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases