3 Combinatorial Chemistry as a Tool for Drug Discovery

Floyd, Christopher D.; Leblanc, Catherine; Whittaker, Mark

doi:10.1016/s0079-6468(08)70046-8

Cited by 49 publications

(23 citation statements)

References 430 publications

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“…The possibility of finding novel lead compounds has been greatly enhanced through the recent developments in combinatorial organic synthesis (Warr, 1997;Dolle and Nelson, 1999;Floyd et al, 1999;Sun, 1999;Borman, 1999aBorman, , 2000 and high throughput screening (HTS) methods (Warr, 1997). As we have discussed, in the present climate of the pharmaceutical industry, the drug discovery process to elicit 'hits' is focused on strategies to evaluate the highest degree of chemical diversity possible in chemical libraries against the respective automated bioassays in order to maximize the coverage of the three-dimensional space of a receptor.…”

Section: The Fit Of Alkaloids In the Drug Discovery Processmentioning

confidence: 99%

The potential of alkaloids in drug discovery

Cordell

Quinn-Beattie

Farnsworth

2001

Phytotherapy Research

328

195

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Section: The Fit Of Alkaloids In the Drug Discovery Processmentioning

confidence: 99%

The potential of alkaloids in drug discovery

Cordell

Quinn-Beattie

Farnsworth

2001

Phytotherapy Research

328

195

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“…In the absence of candidate lead structures, we turned to combinatorial chemistry 22 to identify potential EPO mimetics. Moreover, we adapted an approach whereby candidate ligands were initially screened for EPOr binding, then dimerized in efforts to convert EPOr antagonists into EPOr agonists.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin Mimetics Derived from Solution Phase Combinatorial Libraries

et al. 2001

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The erythropoietin receptor (EPOr) is activated by ligand-induced homodimerization, which leads to the proliferation and differentiation of erythroid progenitors. Through the screening of combinatorial libraries of dimeric iminodiacetic acid diamides, novel small molecule binders of EPOr were identified in a protein binding assay. Evaluation of a series of analogues led to optimization of binding subunits, and these were utilized in the synthesis of higher order dimer, trimer, and tetramer libraries. Several of the most active EPOr binders were found to be partial agonists and induced concentration-dependent proliferation of an EPO-dependent cell line (UT-7/EPO) while having no effect on a cell line lacking the EPOr (FDC-P1). An additional compound library, based on a symmetrical isoindoline-5,6-dicarboxylic acid template and including the optimized binding subunits, was synthesized and screened leading to the identification of additional EPO mimetics.

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“…These compound libraries include sources from natural products or synthetic compound collections. Combinatorial library methods have now played an increasing role in both the identi®cation of the initial lead, and subsequent optimization of the lead compounds (Lam, 1997;Floyd et al, 1999). In the last 5 years, several highly sensitive accurate and reliable high-throughput assays have been developed for screening for protein kinases inhibitors.…”

Section: Lead Identification and Optimizationmentioning

confidence: 99%

Development of inhibitors for protein tyrosine kinases

2000

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In the last 5 years, through combinatorial chemistry, high-throughput screening, computational chemistry, and traditional medicinal chemistry, numerous inhibitors for various protein tyrosine kinases (PTKs) have been developed. The majority of these compounds are small molecules that compete at the ATP binding site of the catalytic domain of the enzymes. Some compounds such as pseudosubstrate-based peptide inhibitor binds to the peptide/protein substrate site of the catalytic domain. Some inhibitors, primarily monoclonal antibodies, bind to the extracellular domain of receptor tyrosine kinases. Some of these inhibitors are highly potent and selective. Several are currently undergoing clinical trials for a number of diseases such as cancer. Oncogene (2000) 19, 5690 ± 5701.

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3 Combinatorial Chemistry as a Tool for Drug Discovery

Cited by 49 publications

References 430 publications

The potential of alkaloids in drug discovery

The potential of alkaloids in drug discovery

Erythropoietin Mimetics Derived from Solution Phase Combinatorial Libraries

Development of inhibitors for protein tyrosine kinases

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