title: A practical use of ligand efficiency indices out of the fragment-based approach: ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors.
abstract: Ligand efficiency is frequently used to evaluate fragment compounds in fragment-based drug discovery. We applied ligand efficiency indices in a conventional virtual screening-initiated lead generation study of soluble epoxide hydrolase inhibitors. From a considerable number of screening hits, we carefully selected a compound exhibiting relatively weak inhibitory activity but high ligand efficiency. This ligand efficiency-guided selection could reveal compounds possessing preferable lead-like characteristics in terms of molecular size and lipophilicity. The following hit-to-lead medicinal chemistry campaign successfully led to a more potent, ADMET-clean, lead-like compound preserving high ligand efficiency. Retrospective analyses, including consideration of the more recently proposed indices of ligand efficiency, shed light on the validity of our hit triage and hit-to-lead studies. The present work proposes a practical methodology for lead generation using the concept of ligand efficiency.
authors.affiliation: Chemistry Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd. 3-1-98 Kasugade-naka, Konohana, Osaka 554-0022, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tanaka
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Takaaki
authors.initials: T
authors.lastname: Shiyama
authors.forename: Tamiki
authors.initials: T
authors.lastname: Nishimura
authors.forename: Naoki
authors.initials: N
authors.lastname: Chiyo
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tominaga
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sawada
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Mimoto
authors.forename: Naoto
authors.initials: N
authors.lastname: Kusunose
mesh_terms: D000818:Animals; D016208:Databases, Factual; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D013237:Stereoisomerism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055815:Young Adult
chemical_list: C575634:4-(3-isopropyl-1,2,4-oxadiazol-5-yl)-N-(trans-2-phenylcyclopropyl)piperidine-1-carboxamide; D008024:Ligands; D010069:Oxadiazoles; D014508:Urea; D004851:Epoxide Hydrolases