title: Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery.
abstract: Analysis of binding energy hot spots at protein surfaces can provide crucial insights into the prospects for successful application of fragment-based drug discovery (FBDD), and whether a fragment hit can be advanced into a high-affinity, drug-like ligand. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. We show that published data are sufficient to provide a sophisticated and quantitative understanding of how hot spots derive from a protein 3D structure, and how their strength, number, and spatial arrangement govern the potential for a surface site to bind to fragment-sized and larger ligands. This improved understanding provides important guidance for the effective application of FBDD in drug discovery.
authors.affiliation: Acpharis Inc., 160 North Mill Street, Holliston, MA 01746, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Hall
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA. Electronic address: midas@bu.edu.
authors.forename: Dima
authors.initials: D
authors.lastname: Kozakov
authors.affiliation: Department of Chemistry, Boston University, Boston, MA, 02215, USA. Electronic address: whitty@bu.edu.
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitty
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA; Department of Chemistry, Boston University, Boston, MA, 02215, USA. Electronic address: vajda@bu.edu.
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
mesh_terms: D001665:Binding Sites; D055808:Drug Discovery; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D008024:Ligands