title: Design of small-sized libraries by combinatorial assembly of linkers and functional groups to a given scaffold: application to the structure-based optimization of a phosphodiesterase 4 inhibitor.
abstract: Combinatorial chemistry and library design have been reconciled by applying simple medicinal chemistry concepts to virtual library design. The herein reported "Scaffold-Linker-Functional Group" (SLF) approach has the aim to maximize diversity while minimizing the size of a scaffold-focused library with the aid of simple molecular variations in order to identify critical pharmacophoric elements. Straightforward rules define the way of assembling three building blocks: a conserved scaffold, a variable linker, and a variable functional group. By carefully selecting a limited number of functional groups not overlapping in pharmacophoric space, the size of the library is kept to a few hundred. As an application of the SLF approach, a small-sized combinatorial library (320 compounds) was derived from the scaffold of the known phosphodiesterase 4 inhibitor zardaverine. The most interesting analogues were further prioritized for synthesis and enzyme inhibition by FlexX docking to the X-ray structure of the enzyme, leading to a 900-fold increased affinity within nine synthesized compounds and a single screening round.
authors.affiliation: Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR CNRS 7081, F-67401 Illkirch, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Krier
authors.forename: João X de
authors.initials: JX
authors.lastname: Araújo-Júnior
authors.forename: Martine
authors.initials: M
authors.lastname: Schmitt
authors.forename: Jérôme
authors.initials: J
authors.lastname: Duranton
authors.forename: Hélène
authors.initials: H
authors.lastname: Justiano-Basaran
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
authors.forename: Didier
authors.initials: D
authors.lastname: Rognan
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D020650:Combinatorial Chemistry Techniques; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016208:Databases, Factual; D015195:Drug Design; D008958:Models, Molecular; D009130:Muscle, Smooth / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C066436:zardaverine