title: Approaches to design non-covalent inhibitors for human granzyme B (hGrB).
abstract: A structure-based design campaign for non-covalent small molecule inhibitors of human granzyme B was carried out by means of a virtual screening strategy employing three constraints and probe site-mapping with FTMAP to identify ligand "hot spots". In addition, new scaffolds of diverse structures were subsequently explored with ROCS shape-based superposition methods, following by Glide SP docking, induced fit docking and analysis of QikProp molecular properties. Novel classes of moderately active small molecule blockers (≥25 μM IC50 values) from commercially available libraries were identified, and three novel scaffolds have been synthesized by multi-step procedures. Furthermore, we provide an example of a comprehensive structure-based drug discovery approach to non-covalent inhibitors that relies on the X-ray structure of a covalently bound ligand and suggest that the design path may be compromised by alternative and unknown binding poses.
authors.affiliation: Department of Chemistry, 1515 Dickey Drive. and Emory University, Atlanta, GA 30322, USA. jsnyder@emory.edu.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Kim
authors.forename: Lauriane A
authors.initials: LA
authors.lastname: Buisson
authors.forename: Dean A
authors.initials: DA
authors.lastname: Heathcote
authors.forename: Haipeng
authors.initials: H
authors.lastname: Hu
authors.forename: D Christopher
authors.initials: DC
authors.lastname: Braddock
authors.forename: Anthony G M
authors.initials: AG
authors.lastname: Barrett
authors.forename: Philip G
authors.initials: PG
authors.lastname: Ashton-Rickardt
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D000465:Algorithms; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D053804:Granzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D015842:Serine Proteinase Inhibitors; D053804:Granzymes