title: Identifying Activity Cliff Generators of PPAR Ligands Using SAS Maps.
abstract: Structure-activity relationships (SAR) of compound databases play a key role in hit identification and lead optimization. In particular, activity cliffs, defined as a pair of structurally similar molecules that present large changes in potency, provide valuable SAR information. Herein, we introduce the concept of activity cliff generator, defined as a molecular structure that has a high probability to form activity cliffs with molecules tested in the same biological assay. To illustrate this concept, we discuss a case study where Structure-Activity Similarity maps were used to systematically identify and analyze activity cliff generators present in a dataset of 168 compounds tested against three peroxisome-proliferator-activated receptor (PPAR) subtypes. Single-target and dual-target activity cliff generators for PPARα and δ were identified. In addition, docking calculations of compounds that were classified as cliff generators helped to suggest a hot spot in the target protein responsible of activity cliffs and to analyze its implication in ligand-enzyme interaction.
authors.affiliation: Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, México DF 04510, Mexico.
authors.forename: Oscar
authors.initials: O
authors.lastname: Méndez-Lucio
authors.affiliation: Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, UAM-X, México, DF 04960, Mexico.
authors.forename: Jaime
authors.initials: J
authors.lastname: Pérez-Villanueva
authors.affiliation: Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, México DF 04510, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Castillo
authors.affiliation: Torrey Pines Institute of Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA tel.: +1 772-345-4685; fax: +1 772-345-3649. jmedina@tpims.org.
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
keywords: Activity cliffs; Activity landscape; Cheminformatics; Molecular similarity; PPAR Agonist; Structure-activity relationships; Structure-activity similarity (SAS) maps