Privileged Motif Research Articles

Target analysis of α-alkylidene-γ-butyrolactones in uropathogenic E. coli

α-Alkylidene-γ-butyrolactones are quite common in nature and exhibit a broad spectrum of biological activities. We therefore synthesized a small library of xanthatine inspired α-alkylidene-γ-butyrolactones to screen non-pathogenic and uropathogenic E. coli strains by activity based protein profiling (ABPP). The identified targets are involved in cellular redox processes and give first insight into the preferred binding sites of this privileged motif. Furthermore the gene of one protein, c2450, which was only identified in uropathogenic E. coli belongs to a genomic island which encodes a hybrid polyketide/non-ribosomal peptide synthetase (PKS/NRPS). This system is responsible for the synthesis of colibactin, a natural product which causes DNA double strand breaks in eukaryotic cells leading to the activation of the DNA damage checkpoint pathway and subsequent cell cycle arrest. While the role of several proteins that are involved in the colibactin synthesis has been elucidated, the function of c2450 remains elusive. Investigation of the binding site showed that c2450 is modified at a cysteine residue which may be important for the catalytic activity.

Cross-project HTS-datamining

Over the years a massive amount of high-throughput screening (HTS) data has been collected, however, the data are mainly utilized for providing lead generation programs with chemical entry points. The comparison of molecular structures and HTS data across many projects allows to identify and validate structural patterns of frequent hitters, i.e. compounds which generate multiple hits in various target families. The identification of frequent hitters is an important component in maintaining a high-quality screening deck and supports project teams in the triaging of HTS hit lists. In addition, frequent hitters will be contrasted with privileged motifs which are believed to show activities in specific target classes only. The talk will also address the question what causes compounds to be frequent hitters, and in-silico prediction methods will be discussed.

The concept of privileged structures in rational drug design: focus on acridine and quinoline scaffolds in neurodegenerative and protozoan diseases

Introduction: For nearly 20 years, privileged structures have offered an optimal source of core scaffolds and capping fragments for the design of combinatorial libraries directed at a broad spectrum of targets. From describing structures promiscuous within a given target family, the concept has evolved to include frameworks that can modulate proteins lacking a strict target class relation.Areas covered: Based on a literature search from 2000 to 2010, we discuss how two privileged motifs, quinolines and acridines, are particularly recurrent in compounds active against two quite different pathologies, neurodegenerative and protozoan diseases.Expert opinion: As privileged structures, quinolines and acridines could improve the productivity of drug discovery projects in the field of neurodegenerative and protozoan diseases. They could be particularly relevant for protozoan diseases because of the importance of cost-effective strategies and less stringent intellectual property concerns. Furthermore, because of their inherent affinity for various targets, privileged structures could offer a viable starting point in the search for novel multi-target ligands. Finally, from a broader perspective, they can serve as effective probes for investigating unknown but interrelated mechanisms of action.

Privileged structure-guided synthesis of quinazoline derivatives as inhibitors of trypanothione reductase

Novel quinazoline-type compounds were designed as inhibitors of the parasite specific enzyme trypanothione reductase (TR), and their biological activities were evaluated. Some of our compounds inhibited TR, showed selectivity for TR over human glutathione reductase, and inhibited parasite growth in vitro. We propose that the quinazoline framework is a privileged structure that can be purposely modified to design novel TR inhibitors. Furthermore, the use of privileged motifs might emerge as an innovative approach to antiparasitic lead candidates.

Preparation of Aryloxetanes and Arylazetidines by Use of an Alkyl−Aryl Suzuki Coupling

The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chemistry. An efficient approach to installing these two modules into aromatic systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.

The selection and design of GPCR ligands: from concept to the clinic.

Virtual screening methods using structure-based, pharmacophore-based and descriptor based protocols may be used to identify ligands for the G-protein coupled receptor target family. A complementary approach is the synthesis and screening of compound libraries designed using privileged motifs and/or based on validated hit molecules. A virtual screening approach based on molecular docking performed with GOLD using a templated homology model and a consensus scoring procedure can identify vasopressin 1a receptor antagonists. In a separate project a library design and synthesis approach based around validated hit GPCR ligands led to the identification of potent oxytocin antagonists. Subsequent optimisation of the initial library compounds has provided compounds that are now being evaluated in the clinic for the treatment of preterm labour.

RECAP--retrosynthetic combinatorial analysis procedure: a powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry.

The use of combinatorial chemistry for the generation of new lead molecules is now a well established strategy in the drug discovery process. Central to the use of combinatorial chemistry is the design and availability of high quality building blocks which are likely to afford hits from the libraries that they generate. Herein we describe "RECAP" (Retrosynthetic Combinatorial Analysis Procedure), a new computational technique designed to address this building block issue. RECAP electronically fragments molecules based on chemical knowledge. When applied to databases of biologically active molecules this allows the identification of building block fragments rich in biologically recognized elements and privileged motifs and structures. This allows the design of building blocks and the synthesis of libraries rich in biological motifs. Application of RECAP to the Derwent World Drug Index (WDI) and the molecular fragments/ building blocks that this generates are discussed. We also describe a WDI fragment knowledge base which we have built which stores the drug motifs and mention its potential application in structure based drug design programs.