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Bioorg Med Chem Lett. 2016 Dec 1;26(23):5792-5796. doi: 10.1016/j.bmcl.2016.10.037. Epub 2016 Oct 13.

Development of pharmacophore models for small molecules targeting RNA: Application to the RNA repeat expansion in myotonic dystrophy type 1.

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Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
Grup d'Enginyeria Molecular (GEM), Institut Químic de Sarrià (IQS)-Universitat Ramon Llull (URL), Barcelona, Catalonia 08017, Spain.


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)exp complex, 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.


Chemical biology; Chemotype; Pharmacophore; RNA; Virtual screening

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