Lead compounds discovered from libraries

Gołębiowski, Adam; Klopfenstein, Sean R.; Portlock, David E.

doi:10.1016/s1367-5931(00)00203-9

Cited by 105 publications

(59 citation statements)

References 70 publications

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“…Based on this point of view, it is of interest to apply to natural products the virtual screening methods (target-and ligand-based virtual screening), which are well-established techniques for identifying new leads [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

VolSurf analysis of pharmacokinetic properties for several antifungal sesquiterpene lactones isolated from Greek Centaurea sp.

Koukoulitsa

Geromichalos

Skaltsa

2005

J Comput Aided Mol Des

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Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) possessing a variety of biological activities, such as cytotoxic, antitumor, antibacterial, and antifungal. The prediction of the pharmacokinetic profile of several antifungal sesquiterpene lactones, isolated from Greek taxa of Centaurea sp., was undertaken in this study using the VolSurf procedure. The molecules were projected on the following pre-calculated ADME models: Caco-2 cell permeability, plasma protein affinity, blood-brain barrier permeation and thermodynamic solubility. The in silico projection revealed a non optimal pharmacokinetic profile for the studied compounds. ADME in silico screening of a semi-synthetic derivatives virtual library has been performed in order to optimize the pharmacokinetic properties. A number of derivatives were proposed as it was predicted to have higher Caco-2 cell permeability, while the pharmacokinetic behaviour regarding BBB penetration, protein binding and solubility was mainly preserved.

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Section: Introductionmentioning

confidence: 99%

VolSurf analysis of pharmacokinetic properties for several antifungal sesquiterpene lactones isolated from Greek Centaurea sp.

Koukoulitsa

Geromichalos

Skaltsa

2005

J Comput Aided Mol Des

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“…T he most crucial criteria to be met in compound library development for medicinal chemistry and chemical biology research are biological relevance (1,2), drug likeness (3)(4)(5)(6)(7), and diversity (8)(9)(10). To meet these criteria usually potential target proteins are clustered into target families on the basis of functional relatedness and amino acid sequence homology (11).…”

mentioning

confidence: 99%

Compound library development guided by protein structure similarity clustering and natural product structure

Koch

Wittenberg

Basu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

199

128

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To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11␤-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.combinatorial chemistry ͉ enzyme inhibition ͉ bioinformatics ͉ chemical biology ͉ ligand-sensing core

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“…Because of the relatively short time combinatorial approaches have been in use, their impact on drug discovery has not been dramatic and few lead compounds have been brought to the clinic. There are nevertheless promising lead compounds found using 'diversity-driven' libraries (Golebiowski et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Combinatorial methods for discovery of peptide ligands which bind to antibody‐like molecules

Tribbick¹,

Rodda²

2002

J of Molecular Recognition

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In the 1980s, new methods of parallel peptide synthesis were used to make large libraries of peptides, which were then screened for binding to Bence-Jones dimers. Subsequent X-ray crystallography of the Bence-Jones proteins, which had been infiltrated with peptide ligand, was used to determine the structural correlate of the binding data. The mode of binding was found to be not predictable and insight was gained into the forces determining how the so-called mimotopes interacted with binding sites.

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Lead compounds discovered from libraries

Cited by 105 publications

References 70 publications

VolSurf analysis of pharmacokinetic properties for several antifungal sesquiterpene lactones isolated from Greek Centaurea sp.

VolSurf analysis of pharmacokinetic properties for several antifungal sesquiterpene lactones isolated from Greek Centaurea sp.

Compound library development guided by protein structure similarity clustering and natural product structure

Combinatorial methods for discovery of peptide ligands which bind to antibody‐like molecules

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