title: New Frontiers in Druggability.
abstract: A powerful early approach to evaluating the druggability of proteins involved determining the hit rate in NMR-based screening of a library of small compounds. Here, we show that a computational analog of this method, based on mapping proteins using small molecules as probes, can reliably reproduce druggability results from NMR-based screening and can provide a more meaningful assessment in cases where the two approaches disagree. We apply the method to a large set of proteins. The results show that, because the method is based on the biophysics of binding rather than on empirical parametrization, meaningful information can be gained about classes of proteins and classes of compounds beyond those resembling validated targets and conventionally druglike ligands. In particular, the method identifies targets that, while not druggable by druglike compounds, may become druggable using compound classes such as macrocycles or other large molecules beyond the rule-of-five limit.
authors.affiliation: Department of Applied Mathematics & Statistics, Stony Brook University , Stony Brook, New York 11794, United States.
authors.forename: Dima
authors.initials: D
authors.lastname: Kozakov
authors.affiliation: Acpharis Inc. , Holliston, Massachusetts 01746, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Hall
authors.forename: Raeanne L
authors.initials: RL
authors.lastname: Napoleon
authors.forename: Christine
authors.initials: C
authors.lastname: Yueh
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitty
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
mesh_terms: D000818:Animals; D017076:Computer-Aided Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy / Q000379:methods; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011487:Protein Conformation; D060066:Protein Interaction Maps / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D047028:Macrocyclic Compounds; D011506:Proteins