Targeted Approaches in Natural Product Lead Discovery

Potterat, Olivier

doi:10.2533/000942906777675263

Cited by 8 publications

(4 citation statements)

References 10 publications

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“…(DSM 17045) displayed remarkable antagonistic activity in an AlphaScreen assay. The extract was subjected to a dereplication process integrating physicochemical data with biological information. , Comparative analysis of the LC/MS-UV data set and the bioactivity plot of the fractionated extract indicated that the activity of the extract was due to a group of quinonic pigments. We report here on the isolation and the chemical and biological characterization of these compounds, which were shown to be new chlorinated angucyclinone derivatives.…”

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confidence: 99%

Chlorocyclinones A−D, Chlorinated Angucyclinones from Streptomyces sp. Strongly Antagonizing Rosiglitazone-Induced PPAR-γ Activation

et al. 2007

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In the course of our screening to identify novel PPAR-gamma modulators for the potential treatment of type 2 diabetes, four new chlorinated angucyclinones, chlorocyclinones A-D ( 1- 4), were isolated from the mycelium of Streptomyces sp. strain DSM 17045. Their structures were established by spectroscopic methods. Chlorocyclinones antagonize rosiglitazone-induced peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation with IC 50's < 0.4 microM in vitro using an AlphaScreen assay and are able to displace rosiglitazone from the PPAR-gamma ligand-binding domain (LBD) in a scintillation proximity assay (SPA). The compounds proved to be active in a cell-based reporter gene assay as well, antagonizing rosiglitazone-induced PPAR-gamma activity with IC 50 values between 0.60 and 7.0 microM. Chlorocyclinone C ( 3) exhibited the most potent activity in all assays.

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confidence: 99%

Chlorocyclinones A−D, Chlorinated Angucyclinones from Streptomyces sp. Strongly Antagonizing Rosiglitazone-Induced PPAR-γ Activation

et al. 2007

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“…We will herein present a selection of NPs that are in various stages of drug development. For further information on NP drug discovery the reader is referred to reviews covering the field [34,41,45,60,62,[64][65][66][67][68][69][70][71][72].…”

Section: Successful Natural Products In Medicinal Chemistry Programsmentioning

confidence: 99%

Role of Natural Products in Drug Discovery

Lachance

Wetzel

Waldmann

2010

Lead Generation Approaches in Drug Discovery

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“…A more targeted approach focuses on innovative technological tools combining analytical and biological information. An overview of recent developments in this area and successful examples thereof are presented by Potterat and Hamburger [18,19]. As soon as the constituent regarded to be responsible for the overall effect is isolated, further research focuses on a molecular level including structure elucidation and pharmacological profiling.…”

Section: Status Of Npsmentioning

confidence: 99%

Virtual screening for the discovery of bioactive natural products

Rollinger

Stuppner

Langer

2008

Natural Compounds as Drugs Volume I

121

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In this survey the impact of the virtual screening concept is discussed in the field of drug discovery from nature. Confronted by a steadily increasing number of secondary metabolites and a growing number of molecular targets relevant in the therapy of human disorders, the huge amount of information needs to be handled. Virtual screening filtering experiments already showed great promise for dealing with large libraries of potential bioactive molecules. It can be utilized for browsing databases for molecules fitting either an established pharmacophore model or a three dimensional (3D) structure of a macromolecular target. However, for the discovery of natural lead candidates the application of this in silico tool has so far almost been neglected. There are several reasons for that. One concerns the scarce availability of natural product (NP) 3D databases in contrast to synthetic libraries; another reason is the problematic compatibility of NPs with modern robotized high throughput screening (HTS) technologies. Further arguments deal with the incalculable availability of pure natural compounds and their often too complex chemistry. Thus research in this field is time-consuming, highly complex, expensive and ineffective. Nevertheless, naturally derived compounds are among the most favorable source of drug candidates. A more rational and economic search for new lead structures from nature must therefore be a priority in order to overcome these problems.Here we demonstrate some basic principles, requirements and limitations of virtual screening strategies and support their applicability in NP research with already performed studies. A sensible exploitation of the molecular diversity of secondary metabolites however asks for virtual screening concepts that are interfaced with well-established strategies from classical pharmacognosy that are used in an effort to maximize their efficacy in drug discovery. Such integrated virtual screening workflows are outlined here and shall help to motivate NP researchers to dare a step towards this powerful in silico tool.

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Targeted Approaches in Natural Product Lead Discovery

Cited by 8 publications

References 10 publications

Chlorocyclinones A−D, Chlorinated Angucyclinones from Streptomyces sp. Strongly Antagonizing Rosiglitazone-Induced PPAR-γ Activation

Chlorocyclinones A−D, Chlorinated Angucyclinones from Streptomyces sp. Strongly Antagonizing Rosiglitazone-Induced PPAR-γ Activation

Role of Natural Products in Drug Discovery

Virtual screening for the discovery of bioactive natural products

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