Mireille Krier, João X de Araújo-Júnior, Martine Schmitt, Jérôme Duranton, Hélène Justiano-Basaran, Claire Lugnier, Jean-Jacques Bourguignon, Didier Rognan
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR CNRS 7081, F-67401 Illkirch, France.
Journal of medicinal chemistry 2005 Jun 2Combinatorial 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.
Mireille Krier, João X de Araújo-Júnior, Martine Schmitt, Jérôme Duranton, Hélène Justiano-Basaran, Claire Lugnier, Jean-Jacques Bourguignon, Didier Rognan. 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. Journal of medicinal chemistry. 2005 Jun 2;48(11):3816-22
PMID: 15916433
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