title: Common pharmacophore of structurally distinct small-molecule inhibitors of intracellular retrograde trafficking of ribosome inactivating proteins.
abstract: We reported previously (±)-2-(5-methylthiophen-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one [(±)-Retro-2(cycl)] as the chemical structure of Retro-2 that showed mouse protection against ricin, a notorious ribosome inactivating protein (RIP). Herein we report our chemical resolution of (±)-Retro-2(cycl), analog synthesis, and cell-based evaluation showing that the two optically pure enantiomers and their achiral analog have nearly the same degree of cell protection against ricin as (±)-Retro-2(cycl). We also report our computational studies explaining the lack of stereo preference and revealing a common pharmacophore of structurally distinct inhibitors of intracellular retrograde trafficking of RIPs. This pharmacophore comprises a central aromatic ring o-substituted by an aromatic ring and a moiety bearing an O or S atom attached to sp² C atom(s). These results offer new insights into lead identification and optimization for RIP antidote development to minimize the global health threat caused by ribosome-inactivating proteins.
authors.affiliation: Computer-Aided Molecular Design Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Shichao
authors.initials: S
authors.lastname: Yu
authors.forename: Jewn Giew
authors.initials: JG
authors.lastname: Park
authors.forename: Jennifer Nielsen
authors.initials: JN
authors.lastname: Kahn
authors.forename: Nilgun E
authors.initials: NE
authors.lastname: Tumer
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D021381:Protein Transport / Q000187:drug effects*; D054788:Ribosome Inactivating Proteins / Q000378:metabolism*; D012276:Ricin / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013237:Stereoisomerism; D014709:Vero Cells
chemical_list: D054852:Small Molecule Libraries; D012276:Ricin; D054788:Ribosome Inactivating Proteins