title: Predicting protein-ligand affinity with a random matrix framework.
abstract: Rapid determination of whether a candidate compound will bind to a particular target receptor remains a stumbling block in drug discovery. We use an approach inspired by random matrix theory to decompose the known ligand set of a target in terms of orthogonal "signals" of salient chemical features, and distinguish these from the much larger set of ligand chemical features that are not relevant for binding to that particular target receptor. After removing the noise caused by finite sampling, we show that the similarity of an unknown ligand to the remaining, cleaned chemical features is a robust predictor of ligand-target affinity, performing as well or better than any algorithm in the published literature. We interpret our algorithm as deriving a model for the binding energy between a target receptor and the set of known ligands, where the underlying binding energy model is related to the classic Ising model in statistical physics.
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; ljc37@cam.ac.uk alphalee@g.harvard.edu.|Kavli Institute of Bionano Science and Technology, Harvard University, Cambridge, MA 02138.
authors.forename: Alpha A
authors.initials: AA
authors.lastname: Lee
authors.affiliation: School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.|Kavli Institute of Bionano Science and Technology, Harvard University, Cambridge, MA 02138.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brenner
authors.affiliation: Department of Chemistry, University of Cambridge, CB2 1EW, Cambridge, United Kingdom ljc37@cam.ac.uk alphalee@g.harvard.edu.
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Colwell
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D008024:Ligands; D008962:Models, Theoretical; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry
chemical_list: D008024:Ligands; D011506:Proteins
keywords: computational pharmacology; drug discovery; protein–ligand affinity; random matrix theory; statistical physics