Virtual screening for the discovery of bioactive natural products

Institute of Pharmacy/Pharmacognosy, Leopold-Franzens University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria.
Fortschritte der Arzneimittelforschung. Progress in drug research. Progrès des recherches pharmaceutiques 02/2008; 65:211, 213-49. DOI: 10.1007/978-3-7643-8117-2_6
Source: PubMed

ABSTRACT 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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    Pharmaceutical Biology 03/2014; 52(8). DOI:10.3109/13880209.2013.874534 · 1.24 Impact Factor
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    • "Accessed 2012) to identify novel inhibitors of HpPPAT that could serve as lead compounds for the design of antibiotics that target H. pylori infection. The vHTS computational screening technique automatically and individually docks compounds from a specified database into the active site of a target protein, and estimates the binding affinity of the target protein toward the docked compound by using scoring functions [25–27]. Two docking programs, CDOCKER [28] and LigandFit [29], were used to screen a large number of compounds that are available in the PubChem compound database. "
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    ABSTRACT: Helicobacter pylori is a major etiologic agent associated with the development and maintenance of human gastritis. The goal of this study was to develop novel antibiotics against H. pylori, and we thus targeted H. pylori phosphopantetheine adenylyltransferase (HpPPAT). PPAT catalyzes the penultimate step in coenzyme A biosynthesis. Its inactivation effectively prevents bacterial viability, making it an attractive target for antibacterial drug discovery. We employed virtual high-throughput screening and the HpPPAT crystal structure to identify compounds in the PubChem database that might act as inhibitors of HpPPAT. d-amethopterin is a potential inhibitor for blocking HpPPAT activity and suppressing H. pylori viability. Following treatment with d-amethopterin, H. pylori exhibited morphological characteristics associated with cell death. d-amethopterin is a mixed inhibitor of HpPPAT activity; it simultaneously occupies the HpPPAT 4'-phosphopantetheine- and ATP-binding sites. Its binding affinity is in the micromolar range, implying that it is sufficiently potent to serve as a lead compound in subsequent drug development. Characterization of the d-amethopterin and HpPPAT interaction network in a docked model will allow us to initiate rational drug optimization to improve the inhibitory efficacy of d-amethopterin. We anticipate that novel, potent, and selective HpPPAT inhibitors will emerge for the treatment of H. pylori infection.
    PLoS ONE 09/2013; 8(9):e74271. DOI:10.1371/journal.pone.0074271 · 3.23 Impact Factor
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    BMC Bioinformatics 12/2011; 12 Suppl 14(Suppl 14):S5. DOI:10.1186/1471-2105-12-S14-S5 · 2.58 Impact Factor
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