title: Development of pharmacophore models for small molecules targeting RNA: Application to the RNA repeat expansion in myotonic dystrophy type 1.
abstract: RNA is an important drug target, but current approaches to identify bioactive small molecules have been engineered primarily for protein targets. Moreover, the identification of small molecules that bind a specific RNA target with sufficient potency remains a challenge. Computer-aided drug design (CADD) and, in particular, ligand-based drug design provide a myriad of tools to identify rapidly new chemical entities for modulating a target based on previous knowledge of active compounds without relying on a ligand complex. Herein we describe pharmacophore virtual screening based on previously reported active molecules that target the toxic RNA that causes myotonic dystrophy type 1 (DM1). DM1-associated defects are caused by sequestration of muscleblind-like 1 protein (MBNL1), an alternative splicing regulator, by expanded CUG repeats (r(CUG)exp). Several small molecules have been found to disrupt the MBNL1-r(CUG)expcomplex, ameliorating DM1 defects. Our pharmacophore model identified a number of potential lead compounds from which we selected 11 compounds to evaluate. Of the 11 compounds, several improved DM1 defects both in vitro and in cells.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Angelbello
authors.affiliation: Grup d'Enginyeria Molecular (GEM), Institut Químic de Sarrià (IQS)-Universitat Ramon Llull (URL), Barcelona, Catalonia 08017, Spain.
authors.forename: Àlex L
authors.initials: ÀL
authors.lastname: González
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Rzuczek
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D017076:Computer-Aided Design; D004268:DNA-Binding Proteins / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D012313:RNA
keywords: Chemical biology; Chemotype; Pharmacophore; RNA; Virtual screening