Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists

Evans, B.; Rittle, Kenneth E.; Bock, Mark G.; DiPardo, Robert M.; Freidinger, Roger; Whitter, Willie L.; Lundell, G. F.; Veber, Daniel F.; Anderson, Paul S.; Chang, Raymond S.L.; Lotti, Victor J.; Cerino, Deborah J.; Chen, T. B.; Kling, Paul J.; Kunkel, K. A.; Springer, James P.; Hirshfield, J.

doi:10.1021/jm00120a002

Cited by 1,395 publications

(772 citation statements)

References 27 publications

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“…Natural products usually interact with multiple proteins during their biosynthesis as well as when they exert their mode of action, which indicates that structural information for protein recognition has been encoded into their molecular structure during evolution. Consequently, the underlying scaffolds of natural products have been recognized as privileged structures for library design for several years and explored in library design [31]. To chart and visualize the chemical space populated by natural products, Waldmann and coworkers [28] introduced a hierarchical classification of their underlying scaffolds that is based on their cyclic frameworks and linkers.…”

Section: Concepts For Small Molecule Synthesismentioning

confidence: 99%

Biology-inspired synthesis of compound libraries

Kaiser

Wetzel

Kumar

et al. 2008

Cell. Mol. Life Sci.

148

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Section: Concepts For Small Molecule Synthesismentioning

confidence: 99%

Biology-inspired synthesis of compound libraries

Kaiser

Wetzel

Kumar

et al. 2008

Cell. Mol. Life Sci.

148

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“…Different methods to search and identify substructures in compound databases have been developed previously [10][11][12][13][14][15][16]. Analysis of substructure contents of ligands for a target family led to the formulation of the privileged substructure concept by Evans et al and Patchett et al [17,18]. These substructures are often used to build up target familyselective screening libraries.…”

Section: Introductionmentioning

confidence: 99%

Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept

et al. 2009

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Success in small molecule screening relies heavily on the preselection of compounds. Here, we present a strategy for the enrichment of chemical libraries with potentially bioactive compounds integrating the collected knowledge of medicinal chemistry. Employing a genetic algorithm, substructures typically occurring in bioactive compounds were identified using the World Drug Index. Availability of compounds containing the selected substructures was analysed in vendor libraries, and the substructure-specific sublibraries were assembled. Compounds containing reactive, undesired functional groups were omitted. Using a diversity filter for both physico-chemical properties and the substructure composition, the compounds of all the sublibraries were ranked. Accordingly, a screening collection of 16,671 compounds was selected. Diversity and chemical space coverage of the collection indicate that it is highly diverse and well-placed in the chemical space spanned by bioactive com-

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“…In addition, some chemical motifs are associated with high biological activity and often confer activity against more than one target/receptor (11)(12)(13)(14)(15)(16). These motifs have been referred to as ''privileged structures'' (11).…”

mentioning

confidence: 99%

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

Bisson

Cheltsov

Bruey-Sédano

et al. 2007

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

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Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico ''drug repurposing'' procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation. The phenothiazine derivatives acetophenazine, fluphenazine, and periciazine, used clinically as antipsychotic drugs, were identified as weak AR antagonists. This in vitro biological activity correlated well with endocrine side effects observed in individuals taking these medications. Further computational optimization of phenothiazines, combined with in vitro screening, led to the identification of a nonsteroidal antiandrogen with improved AR antagonism and marked reduction in affinity for dopaminergic and serotonergic receptors that are the primary target of phenothiazine antipsychotics.androgen receptor ͉ drug design ͉ prostate cancer C urrent approaches for discovery of novel chemical leads against a molecular target rely heavily on high-throughput screening (HTS) and to a lesser extent on virtual ligand screening (VLS) techniques. HTS has provided rapid lead identification for numerous drug targets (1-8); however, HTS also has major drawbacks, including a significant level of false positives and false negatives and low hit rates for many targets (9). Successful leads from HTS can also suffer from poor bioavailability and unwanted toxicity profiles of compounds. These problems result partially from the nature of the chemical libraries used for HTS. Furthermore, because the pharmacological properties of most compound libraries are largely unknown, there is an additional high risk that optimization of hits identified with HTS will not be sufficient for their evolution into real drugs.In contrast, retrospective analysis of marketed drugs reveals that their physicochemical and structural properties are clustered around preferred values and scaffolds (10). In addition, some chemical motifs are associated with high biological activity and often confer activity against more than one target/receptor (11-16). These motifs have been referred to as ''privileged structures'' (11). These observations lead to an assumption that the chemical space of potential drugs is limited. Consequently, currently marketed...

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Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists

Cited by 1,395 publications

References 27 publications

Biology-inspired synthesis of compound libraries

Biology-inspired synthesis of compound libraries

Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

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