title: A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology.
abstract: Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in drug discovery. The rational design of drugs that act via polypharmacological mechanisms can produce compounds that exhibit increased therapeutic potency and against which resistance is less likely to develop. Additionally, identifying multiple protein targets is also critical for side-effect prediction. One third of potential therapeutic compounds fail in clinical trials or are later removed from the market due to unacceptable side effects often caused by off-target binding. In the current work, we introduce a multidimensional strategy for the identification of secondary targets of known small-molecule inhibitors in the absence of global structural and sequence homology with the primary target protein. To demonstrate the utility of the strategy, we identify several targets of 4,5-dihydroxy-3-(1-naphthyldiazenyl)-2,7-naphthalenedisulfonic acid, a known micromolar inhibitor of Trypanosoma brucei RNA editing ligase 1. As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology.
authors.affiliation: Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America. jdurrant@ucsd.edu
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durrant
authors.forename: Rommie E
authors.initials: RE
authors.lastname: Amaro
authors.forename: Lei
authors.initials: L
authors.lastname: Xie
authors.forename: Michael D
authors.initials: MD
authors.lastname: Urbaniak
authors.forename: Michael A J
authors.initials: MA
authors.lastname: Ferguson
authors.forename: Antti
authors.initials: A
authors.lastname: Haapalainen
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Chen
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Di Guilmi
authors.forename: Frank
authors.initials: F
authors.lastname: Wunder
authors.forename: Philip E
authors.initials: PE
authors.lastname: Bourne
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000465:Algorithms; D020134:Catalytic Domain; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D030562:Databases, Protein; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008954:Models, Biological; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein
chemical_list: D011506:Proteins