Discovery of Thrombin Inhibitor Fragments from Chemical Microarray Screening

Neumann, Thomas; Junker, Hans‐Dieter; Keil, Oliver; Burkert, Klaus; Ottleben, Holger; Gamer, Jürgen; Sekul, Renate; Deppe, H.; Feurer, Achim; Tomandl, Dirk; Metz, Günther

doi:10.2174/157018005774717343

Cited by 31 publications

(24 citation statements)

References 5 publications

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“…Furthermore, there are also a few examples of neutral P1 moieties such as benzothiophene and hydroxybenzothiophene [194][195][196], cyclohexylmethyl, benzyl and dichlorobenzyl [197], 3-chlorobenzyl and 2-oxyacetamide-5-chlorobenzyl [38,198], phenol [33], tryptophan [199] and 6-fluorotryptamine [200]. As one of the most recent examples, screening of a fragment-based compound library also resulted in the discovery of thrombin-binding fragments with a nonbasic P1 motif [201]. However, only some chlorobenzyl-based inhibitors and a few hydroxybenzothiophene derivatives such as inhibitor 42 (K i = 0.3 nM; Fig.…”

Section: New Inhibitors -Old Principlesmentioning

confidence: 99%

Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

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Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could, therefore, be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. However, development of direct thrombin inhibitors has brought researchers more heartache than success. The most recent setback came this year when AstraZeneca withdrew Ximelagatran, the first orally bioavailable direct thrombin inhibitor that had received regulatory approval (France, 2003), after reports of serious hepatoxicity in a fraction of patients. This review describes the status of direct thrombin inhibitors, focusing on drug candidates that are at present in clinical trials. In addition, some more recent research strategies in the design of novel direct thrombin inhibitors are discussed, which may very well contribute to future developments of potent anticoagulants.

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Section: New Inhibitors -Old Principlesmentioning

confidence: 99%

Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

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“…The synthesized compound collection was spatially immobilized on SAM-based microarrays by using a highly standardized procedure in combination with extensive quality control steps and a high degree of automation [26]. This microarray based low affinity screening platform is currently in use for customer and in-house drug discovery projects, leading to the identification of new fragments and lead-like compounds in different protein classes [27,28]. 1 1 2 26 100 28 25 1 14 70 94 24 2 1 4 47 74 9 26 1 16 65 100 12 3 1 6 59 100 19 27 1 18 60 58 20 4 1 8 75 100 31 28 1 20 58 100 13 5 1 10 59 95 15 29 1 22 64 100 29 6 1 12 57 98 34 30 1 24 62 98 46 7 2 1 62 96 23 31 2 13 56 100 35 8 2 3 65...…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Quality Control of Thiol Tagged Compound Libraries for Chemical Microarrays

Maier¹,

Mathur²,

Rau³

et al. 2006

QSAR Comb. Sci.

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A method for the synthesis and quality control of compound collections containing reactive thiol functions was developed. Such libraries form the basis for the construction of chemical microarrays to be used in fragment-based screening. Amino-modified polymer membranes fixed into the wells of microtiter plates were used as the solid phase for the nanomole-scale synthesis of a thiol-tagged small molecule library using a spatial onecompound/one-well strategy. A thiolselective Liquid Chromatography-Mass Spectroscopy (LC-MS) protocol of each compound before attachment to the microarray surface was established, allowing an exact determination of compound purity and concentration. The established synthesis and quality control method is an important prerequisite for an accurate read-out of the array compound -target interaction data, and simplifies the usage of small molecule microarrays for low affinity screening.

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“…In this unique set-up, the target protein is incubated with the chemical microarray, resulting in much higher response signals that are detected in a highthroughput fashion (for each campaign, 24,000 fragments and 86,000 lead-like compounds are screened). This approach is suitable for fragment screening and has been used in the discovery of thrombin [187] and MMP13 [188] inhibitors.…”

Section: Surface Plasmon Resonance (Spr)mentioning

confidence: 99%

Fragment-Based Drug Design: Computational and Experimental State of the Art

Hoffer¹,

Renaud²,

Horvath

2011

CCHTS

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Fragment-based screening is an emerging technology which is used as an alternative to high-throughput screening (HTS), and often in parallel. Fragment screening focuses on very small compounds. Because of their small size and simplicity, fragments exhibit a low to medium binding affinity (mM to µM) and must therefore be screened at high concentration in order to detect binding events. Since some issues are associated with high-concentration screening in biochemical assays, biophysical methods are generally employed in fragment screening campaigns. Moreover, these techniques are very sensitive and some of them can give precise information about the binding mode of fragments, which facilitates the mandatory hit-to-lead optimization. One of the main advantages of fragment-based screening is that fragment hits generally exhibit a strong binding with respect to their size, and their subsequent optimization should lead to compounds with better pharmacokinetic properties compared to molecules evolved from HTS hits. In other words, fragments are interesting starting points for drug discovery projects. Besides, the chemical space of low-complexity compounds is very limited in comparison to that of drug-like molecules, and thus easier to explore with a screening library of limited size. Furthermore, the "combinatorial explosion" effect ensures that the resulting combinations of interlinked binding fragments may cover a significant part of "drug-like" chemical space. In parallel to experimental screening, virtual screening techniques, dedicated to fragments or wider compounds, are gaining momentum in order to further reduce the number of compounds to test. This article is a review of the latest news in both experimental and in silico virtual screening in the fragment-based discovery field. Given the specificity of this journal, special attention will be given to fragment library design.

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Discovery of Thrombin Inhibitor Fragments from Chemical Microarray Screening

Cited by 31 publications

References 5 publications

Direct thrombin inhibitors – a survey of recent developments

Direct thrombin inhibitors – a survey of recent developments

Synthesis and Quality Control of Thiol Tagged Compound Libraries for Chemical Microarrays

Fragment-Based Drug Design: Computational and Experimental State of the Art

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