title: The importance of hydration thermodynamics in fragment-to-lead optimization.
abstract: Using a computational approach to assess changes in solvation thermodynamics upon ligand binding, we investigated the effects of water molecules on the binding energetics of over 20 fragment hits and their corresponding optimized lead compounds. Binding activity and X-ray crystallographic data of published fragment-to-lead optimization studies from various therapeutically relevant targets were studied. The analysis reveals a distinct difference between the thermodynamic profile of water molecules displaced by fragment hits and those displaced by the corresponding optimized lead compounds. Specifically, fragment hits tend to displace water molecules with notably unfavorable excess entropies-configurationally constrained water molecules-relative to those displaced by the newly added moieties of the lead compound during the course of fragment-to-lead optimization. Herein we describe the details of this analysis with the goal of providing practical guidelines for exploiting thermodynamic signatures of binding site water molecules in the context of fragment-to-lead optimization.
authors.affiliation: Schrödinger K.K., 17F Marunouchi Trust Tower North, 1-8-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005 (Japan). osamu.ichihara@schrodinger.com.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ichihara
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Shimada
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshidome
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D014867:Water; D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2; D053829:Amyloid Precursor Protein Secretases
keywords: druggability; fragment-based drug design; hot spot; hydrophobic effect; protein hydration thermodynamics