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In Silico Screening Major Spice Phytochemicals for Their Novel Biological Activity and Pharmacological Fitness Riju A*, Sithara K, Suja S

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In Silico Screening Major Spice Phytochemicals for Their Novel Biological Activity and Pharmacological Fitness Riju A*, Sithara K, Suja S Journal of Bioequivalence & Bioavailability - Open Access Research Article JBB/Vol.1 July-August 2009 In Silico Screening Major Spice Phytochemicals for their Novel Biological Activity and Pharmacological Fitness Riju A*, Sithara K, Suja S. Nair, Shamina A and Santhosh J. Eapen Bioinformatics Centre, Indian Institute of Spices Research, Calicut, Kerala 673 012 *Corresponding author: Riju A, Bioinformatics Centre, Indian Institute of Spices Research, Calicut, Kerala 673 012, Tel: 04952731566; E-mail: [email protected] Received June 27, 2009; Accepted August 27, 2009; Published August 28, 2009 Citation: Riju A, Sithara K, Nair SS, Shamina A, Eapen SJ (2009) In Silico Screening Major Spice Phytochemicals for their Novel Biological Activity and Pharmacological Fitness. J Bioequiv Availab 1: 063-073. doi:10.4172/jbb.1000010 Copyright: © 2009 Riju A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Spices have been known for ages as effective therapeutic food. The power of spices to impart biological activity is now slowly reemerging as an area of interest. We have screened 328 compounds present in five major spices namely, cinnamon (Cinnamomum verum), nutmeg (Myristica fragrans), garcinia (Garcinia cambogia), allspice (Pimenta dioica) and black pepper (Piper nigrum L.) for their biological activity as promising therapeutic com- pounds. Out of 328 compounds analyzed, ascorbic acid, nonaldehyde, delphinidin, malabaricone-B, malabaricone- C, isoquercitrin, quercitrin, α-bisabolol, cis-nerolidol, γ-eudesmol, hexan-1-ol and n-octanal were reported as non- carcinogenic and non-mutagenic phytochemicals. Biological activity such as antiinflammatory, antioxidant, anti- viral (HIV), antitoxic, free radical scavenging, cardioprotectant, hepatoprotectant, antitussive, antihemorrhagic etc. were reported for these compounds. Drug likeness of the compounds were checked with WDI rule and Lipinski’s rule of 5. Since the drug research starts with identification of a ‘lead molecule’ with required biological activity, wide range of biological actions along with tox free findings may be efficiently used to develop lead candidate for human health benefits. The results of the study have been developed as a database. This can be accessed through www.spices.res.in/passcom. Keywords: Phytochemicals; Biological activity; Drug likeness; In silico ADMET Introduction A spice is a dried seed, fruit, root, bark or vegetative ized. Since 1960’s, experience in medicinal chemistry has substance used in nutritionally insignificant quantities as shown that the rigorous application of quantitative struc- a food additive for the purpose of flavoring, and some- ture-activity relationship (QSAR) methods to homoge- times as a preservative by killing or preventing the growth neous classes of chemicals inducing the same type of bio- of harmful bacteria. Many of these substances are also logical activity permits formulation of efficient quantita- used for other purposes, such as medicine, religious, ritu- tive models. These QSAR models contribute both to the als, cosmetics, perfumery or as vegetables. Spices in gen- elucidation of the action mechanisms and to the predic- eral are carminative. The indigenous system of medicine tion of the biological activity of yet untested chemicals has given an extra special place to spices because of their (Hansch, 1990). The use of QSAR methods has been ex- unique medicinal properties. The power of spices to im- ported from medicinal chemistry, where they presently part biological activity is now slowly reemerging as an constitute a basic building block in the design of new area of interest. drugs, to the study of biological activities, including tox- icity. The use of computational tools in the prediction of ADME/Tox properties of compounds is growing rapidly Numerous examples exist of drugs being withdrawn in drug discovery as the benefits they provide in high because of unacceptable toxicity in clinical trials and even throughput and early application in drug design are real- after reaching the market-place. If these expensive fail- J Bioequiv Availab Volume 1(2): 063-073 (2009) - 063 ISSN:0975-0851 JBB, an open access journal Journal of Bioequivalence & Bioavailability - Open Access Research Article JBB/Vol.1 July-August 2009 ures can be identified and eliminated early in the drug lite (Metabolic activation by rat liver 10% homogenate, discovery process, there is considerable scope for improv- +S9) and without consideration of metabolite (no meta- ing the efficiency and cost effectiveness of the industry. bolic activation, -S9). The actual value of the prediction The maxim ‘Fail early, fail fast, fail cheaply’ is now firmly result is “positive” or “negative”. The carcinogenicity was embedded in the minds of all drug discovery research predicted based on the result from its model, which is built managers. Since a typical drug takes 10–12 years, and from the data of NTP (National Toxicology Program) and costs up to US$500 million, to reach the market, it is im- US FDA. Of the 328 compounds only 12 compounds were portant to discover its potential toxicity at an early stage. non-mutagenic and non-carcinogenic, all others showed With the advent of cheminformatics tools and accuracy in toxicity either as mutagen or carcinogen. The 12 non-toxic predicting the toxicity in silico, the cost has reduced dra- compounds are ascorbic-acid, nonaldehyde, delphinidin, matically. malabaricone-b, malabaricone-c, isoquercitrin, quercitrin, α-bisabolol, cis-nerolidol, γ-eudesmol, hexan-1-ol and n- Materials and Methods octanal. The healing activity of malabaricone B and A total of 328 compounds present in five major spices malabaricone C, the major antioxidant constituents of the cinnamon (Cinnamomum verum), nutmeg (Myristica spice Myristica malabarica against the indomethacin-in- fragrans), garcinia (Garcinia cambogia), allspice (Pimenta duced gastric ulceration in mice was reported earlier dioica L.) and black pepper (Piper nigrum L.) were (Banerjee et al., 2008). α-Bisabolol has antibacterial and screened for their biological activity for use as promising antifungal activities, an indication of its defensive func- therapeutic compounds. The structure of these chemical tions in plants (Mitova et al., 2003). It has promising ac- compounds were obtained from PubChem (http:// tivity against gram–negative and gram–positive bacteria. pubchem.ncbi.nlm.nih.gov/) and ChemSpider (http:// α-Bisabolol has long been used in cosmetics for its anti- www.chemspider.com/) and each chemical compound was inflammatory, healing and soothing and anti-microbial drawn with chemical drawing tools such as ACD/ properties. α-Bisabolol is well suited for use in skin care ChemSketch and saved in the ‘.mol’ file format. The bio- preparations and can be useful in both sensitive skin and logical activities of the compounds were predicted indi- child/ baby products as a soothing agent. Delphinidin pos- vidually with the help of PASS (Predicted Activity Spec- sesses antioxidant, anti-inflammatory, and antiangiogenic trum for Substances) server (http://195.178.207.233/ properties and is reported as a novel agent against human PASS/). ADME/T (Absorption Distribution Metabolism prostatecancer (PCa) (Hafeez et al., 2008). α -Bisabolol, Excretion and Toxicity) properties were analyzed through was found to have a strong time- and dose-dependent cy- computational methods such as PreADMET server (http:/ totoxic effect on human and rat glioma cells (Elisabetta et /preadmet.bmdrc.org/) and Discoverygate database al., 2004). Quercetrin and isoquercitrin are effective eosi- browser (https://www.discoverygate.com). Drug likeness nophilic in?ammation suppressors, suggesting a potential of the compounds was tested with WDI rule and Lipinski’s for treating allergies (Rogerio et al., 2007). Apart from rule of 5. these we have identified compounds with biological ac- tivities such as antioxidant, antiviral (HIV), antitoxic, free Results and Discussion radical scavenging, cardioprotectant, hepatoprotectant, antitussive, antihemorrhagic, immunostimulant etc. Im- Biological activity is one of the most important charac- portant predicted activities of each compound is list in teristics of a chemical compound reflecting its interaction Table 2. Drug likeness of the compounds were checked with living organisms. Three hundred and twenty eight by WDI rule and Lipinski’s rule of 5. Since drug research compounds present in five major spices selected for this starts with identification of a ‘lead molecule’ with required study have been listed in Table 1. The biological activi- biological activity, a wide range of biological actions along ties of each compound were predicted individually with with tox free findings may be efficiently used to develop the help of PASS (Predicted Activity Spectrum for Sub- lead candidates for human health benefits. The effects stances) server (Filimonov and Poroikov, 1996). ADME/.T described herein, as well as those observed by others in- (Absorption Distribution Metabolism Excretion and Tox- vestigators, together with the broad spectrum of the bio- icity) properties were analyzed through computational logical effects of these substances, strongly suggest that methods such as PreADMET server and Discoverygate the compounds mentioned above have various therapeu- database
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