title: Structure-based maximal affinity model predicts small-molecule druggability.
abstract: Lead generation is a major hurdle in small-molecule drug discovery, with an estimated 60% of projects failing from lack of lead matter or difficulty in optimizing leads for drug-like properties. It would be valuable to identify these less-druggable targets before incurring substantial expenditure and effort. Here we show that a model-based approach using basic biophysical principles yields good prediction of druggability based solely on the crystal structure of the target binding site. We quantitatively estimate the maximal affinity achievable by a drug-like molecule, and we show that these calculated values correlate with drug discovery outcomes. We experimentally test two predictions using high-throughput screening of a diverse compound collection. The collective results highlight the utility of our approach as well as strategies for tackling difficult targets.
authors.affiliation: Department of Molecular Informatics, Research Technology Center, Pfizer Global Research & Development, Cambridge, Massachusetts 02139, USA. alan.cheng@amgen.com
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Coleman
authors.forename: Kathleen T
authors.initials: KT
authors.lastname: Smyth
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.forename: Patricia
authors.initials: P
authors.lastname: Soulard
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Caffrey
authors.forename: Anna C
authors.initials: AC
authors.lastname: Salzberg
authors.forename: Enoch S
authors.initials: ES
authors.lastname: Huang
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D008956:Models, Chemical; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins