Virtual screening for the discovery of bioactive natural products.
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.
- SourceAvailable from: Mamoon Ur Rashid[Show abstract] [Hide abstract]
ABSTRACT: Abstract Context: Trypanosoma brucei brucei (T.b. brucei) infection causes death in cattle, while the current treatments have serious toxicity problems. However, natural products can be used to overcome the problems associated with parasitic diseases including T.b. brucei. Objective: Artemisia elegantissima Pamp (Asteraceae) was evaluated phytochemically for its constituents and antitrypanosomal potential against T.b. brucei for the first time. Scopoletin isolated from A. elegantissima has shown better potential then the standard drug suramin, used against T.b. brucei. Materials and methods: The ethanol extract of the aerial parts of A. elegantissima was fractionated by column and preparative thin-layer chromatography into six fractions (A-F) yielding 13 compounds, these were evaluated for their antitrypanosomal activity against T.b. brucei at different concentrations. Results: Thirteen compounds were isolated from A. elegantissima: (Z)-p-hydroxy cinnamic acid, stigmasterol, β-sitosterol, betulinic acid, bis-dracunculin, dracunculin, scopoletin, apigenin, dihydroluteolin, scoparol, nepetin, bonanzin, and 3',4'-dihydroxy bonanzin. The fractions D-F were found to be active at the concentration of 20 µg/ml and three compounds isolated from these fractions, scopoletin (MIC ≤0.19 µg/ml), 3',4'-dihydroxy bonanzin (MIC = 6.25 µg/ml) and bonanzin (MIC = 20 µg/ml), were found to be highly active. Discussion and conclusion: Artemisia elegantissima was phytochemically and biologically explored for its antitrypanosomal potential against T.b. brucei. The number and orientation of phenolic hydroxyl groups play an important role in the antitrypanosomal potential of coumarins and flavonoids. The compounds 3',4'-dihydroxy bonanzin and scopoletin with low MIC values, hold potential for use as antitrypanosomal drug leads.Pharmaceutical Biology 03/2014; DOI:10.3109/13880209.2013.874534
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ABSTRACT: The use of drug substances derived from plants, fungi, bacteria, and marine organisms are “Mother Nature Gift” for diseases of mankind. Many of these are discovered serendipitously and have a long tradition in medicine. Till date, the use of natural products, their semisynthetic and synthetic derivatives have been mostly confined to their ethnic use. But it has been well known that each substance has a wide spectrum of biological activities as evident from some new uses of many old drugs. PASS (Prediction of Activity Spectra for Substances) has been employed as a strong potential tool to predict the biological activity spectrum of synthetic substances for the discovery of new drugs. But the potential of PASS to predict the biological activity spectra of natural products is still underestimated. The present study was therefore undertaken to investigate and correlate the biological activity spectrum of the main phytoconstituent of some selected Indian medicinal plants with their reported biological activities in order to evaluate the applicability of PASS. Further, the unexplored but PASS-predicted activities having good activity score (Pa>0.7) for particular structure were listed as hidden potential of the plant. KeywordsAyurveda–Biological activity spectrum–Herbal drugs–Natural products–PASSMedicinal Chemistry Research 04/2011; 20(9):1509-1514. DOI:10.1007/s00044-010-9398-y
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ABSTRACT: Androgen receptor (AR) signaling is critical for prostate cancer progression. This has provided the rationale for the use of androgen ablation therapy, involving either surgical or chemical castration, to reduce androgen production and antiandrogen agents to antagonize androgen activity. Flutamide, nilutamide, and bicalutamide represent the main nonsteroidal antiandrogens currently used in practice. However, their efficacy is limited by progression of prostate cancer from hormone-responsive to hormone-refractory phenotype, where cancer cells become resistant to androgen ablation therapy. The most common treatment for hormone-refractory prostate cancer (HRPC) include docetaxel-based chemotherapy, which can lead to a modest improvement in the overall survival, underscoring the urgent need for novel therapeutics for advanced prostate cancer. As the vast majority of HRPC cells overexpress AR and remain dependent on AR signaling, there are considerable ongoing efforts to identify novel AR antagonists. Several novel antiandrogens, including MDV-3100, BMS–641988 and VN/124-1, and CYP17a inhibitors such as abiraterone acetates, are under clinical trials for the management of HRPC. In this chapter, we have reviewed the current state of the development of AR antagonists, with emphasis on those derived from herbal medicinal products, including from Chinese traditional medicine. The current progress in building chemical databases of natural products has provided opportunities for mining natural products against AR by using integrative in silico tools. Reinforcement of this trend will lead to discovery of novel natural product-derived antiandrogens with effectiveness against HRPC.