Vol.

: 01 Issue: 05 April 2007

Reverse Pharmacognosy In New Drug Discovery

Khan Md. Yaseen*1, Kumar Vimal1, Gajjar Anuradha2, Vyas Niraj1, Panchal Siddharth1 and Butani Amee1
1: Dept. of Phytopharmaceuticals and Natural Products, Institute of Pharmacy, Nirma University of Science and Technology, S.G. highway, Ahmedabad, (Gujarat), India. 2: Dept. of Pharmaceutical chemistry, Institute of Pharmacy, Nirma University of Science and Technology, S.G. highway, Ahmedabad, (Gujarat), India.

Abstract: The development of a new drug is a long and costly process. Determination of in vivo activity of a natural drug with is also a challenging work. Reverse pharmacognosy aim toward finding of new biological targets for natural compounds by virtual or real screening and identifying natural resources that contain the active molecules. Reverse pharmacognosy utilizes techniques, such as high-throughput screening (HTS), virtual screening and a knowledge database containing the traditional uses of plants. Pharmacognosy uses plants to discover new bio-active compounds whereas Reverse Pharmacognosy uses natural chemicals to find new plant properties. Integrating pharmacognosy and reverse pharmacognosy in the research process may provide an efficient and rapid tool for natural drug discovery.

Keywords: Pharmacognosy, Reverse Pharmacognosy, Virtual screening, Drug discovery.

*Corresponding Address: Khan Md. Yaseen, Department of Phytopharmaceuticals and Natural Products, Institute of Pharmacy, Nirma University of Science and Technology, S.G. highway, Ahmedabad- 382 481 (Gujarat), India Email: mohammadyaseenkhan@gmail.com

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INTRODUCTION: Alternative systems of medicine viz. Ayurveda, Siddha and Chinese Medicine have become more popular in recent years and have proven their significance in medical sciences1. Pharmacognosy is the branch of extracting new chemical entities from plant and animal origins, but how traditional formulations act is now becoming challenging to scientist and pharmacologists. A survey in 2001 demonstrated that the development of a new drug is a long and costly process; from target validation to regulatory approval it takes an average of 15 years and costs US $880 million2. Combining the strength of knowledge based on traditional systems such as ayurveda with the dramatic power of combinatorial sciences and high-throughput screening (HTS) will help in the generation of structure activity libraries. The three main hurdles in the drug development to provide new functional leads are time, money and toxicity which can be reduced by ayurvedic knowledge and experimental database3. High-throughput screening (HTS) for biological testing and combinatorial chemistry to generate potential hits are the various efforts to accelerate and rationalize drug discovery, but these techniques have not able to increase the discovery of new herbal molecules that are active in vivo4,5. Pharmacognosy, ethnopharmacology and phytochemistry are various branches which have contributed to the discovery of new biologically active natural entities6-9. Many studies have been done which favor integrating traditional knowledge into user friendly databases help the early drug discovery stages10, 11. The review will focus on the technique used in reverse pharmacognosy along with its importance in natural drug discovery. PHARMACOGNOSY: Pharmacognosy is the study of medicinal plants and their extracts, constituents, and phytochemistry. It consist of the following steps Selection of plants Plants are selected on Ethnopharmacological knowledge when specific therapeutic area is desired for treatment. Using knowledge from different cultures increases the probability and ability to identify effective materials that correspond to the therapeutic area. One important consideration is the availability for sufficient quantities of samples for testing and subsequent development12. Extraction Extraction can be defined as a process of removal of soluble materials from an insoluble residue, either liquid or solid, by treatment with a liquid solvent. Extraction is generally done by solvents of different polarity13. Biological evaluation When the estimation of potency of crude drug or its preparation is done by means of its effect on living organisms like bacteria, fungal growth or entire animal, it is known as bioassay. Herbal drugs are screened for their activity by bioassay14. Characterization Isolation of active compounds from the extract is an important step; it is generally done by chromatographic techniques like TLC, HPTLC and HPLC. Main constituents of the drug are studied with the aid of HPTLC and modern spectroscopic techniques, using HPLC-coupled spectroscopic techniques such as HPLC-UV, HPLC-MS as well as HPLC-NMR15, 16. REVERSE PHARMACOGNOSY: Reverse pharmacognosy is a new concept of finding new biological targets from structurally similar chemicals and finally finding the natural sources of the biologically active natural compound which contain them. Various parts of Reverse Pharmacognosy: Structural database for natural compounds Natural compounds that appear in the published literature and compounds found in commercial databases forms the structural database also called Virtual Chemical Database (VCDB). The sources of these compounds are available, and frequently the method applied for their extraction is also described. CONCORD is aVCDB contains more than 100,000 natural compounds, along with their 3D coordinates. Chemical diversity of the compound is the final criterion for the selection of compounds for virtual screening. Target database The target database is composed of 3D protein structures, determined by X-ray crystallography or by homology modeling. The majority of the structures are from humans, although it also contains proteins from other sources (eg. viruses, bacteria). Protein/ligand pair interaction energy is obtained

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and involves retrieval of active ligands from a set of 100 non active compounds; method is explained in detailed by Greenpharma17. Virtual screening tools The basic goal of virtual screening is the reduction of the enormous virtual chemical space of small organic molecules, to synthesize and screen against a specific target protein, to a manageable number of compounds that exhibit the highest chance to lead to a drug candidate. There are two methods for virtual screening : screening based on ligand properties, i.e physicochemical properties (onedimensional data), fragmental description (two-dimensional data) and pharmacophores (3D data) which are techniques of quantitative structure-activity relationship (QSAR)18-20 and screening based on target properties, which requires knowledge of the 3D structure of the target and the ligand which are techniques of de novo design and docking, which involves generating new ligands or adjusting ligands in the active site of the target, respectively21-24. Ethnopharmacological database (ETPHDB) In order to develop botanical data, natural chemical structures, biological testings of extracts and compounds, ETPHDB has been developed. Family, genus, species, common names and synonyms of the plants are included in this database. The database accelerates the discovery of bioactive ingredients e.g. anti inflammatory compounds11.The ETPHDB contains botanical information on plants and their traditional uses, and phytochemistry data associated with biological activity of plants, database allows being a link between plants, molecule and activity.

Fig. 1: Block representation of Reverse Pharmacognosy The simple arrows represent the information flow, while the bold dark arrows correspond to the process flow. Data from an ethnopharmacological database (ETPHDB) are utilized for 'knowledge validation' in converting virtual hits to real hits, and to retrieve the sources of compounds.

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The experimental validation process consists of internal biological tests and/or data gathered from scientific literature. Real hits or real inactive candidates enable the validation of the target models. Comparison of Pharmacognosy and Reverse Pharmacognosy:

Fig. 2: Pharmacognosy and reverse pharmacognosy. The starting material for pharmacognosy is raw plants selected by considering their traditional uses or by biodiversity. Extracts are made from the plants and screened on biological assays to find active ones. The active compound(s) are characterized by an iterative bio-guided fractionation. So pharmacognosy starts with plants and ends with molecules. Reverse pharmacognosy may be undertaken with or without a virtual component. Molecules are selected by chemical diversity. They are screened on several biological assays. Then with the help of compound source database, plants containing bioactive molecules can be determined. Docking and inverse-docking software can be introduced prior to the biological screenings. This step enables to find ligand/target pairs, thereby reducing drastically the number of compounds to be evaluated and the number of biological assays. The natural sources are then identified by compound source database. Reverse pharmacognosy begins with molecules to get bioactive plants with their biological activity characterized at the molecular level. Traditional Knowledge Digital Library (TKDL): In order to prevent grant of patents based on Indian Traditional Knowledge, Government of India has undertaken an ambitious project of creating a Traditional Knowledge Digital Library. This is a joint venture of the Council of Scientific Research and Central Council for Research in Ayurveda & Siddha. This project is intended to cover about 35,000 formulations available in 14 classical texts of Ayurveda to convert the information in to patent compatible format. The work has been initiated with a cooperative set up of 30 Ayurveda experts, 5 Information Technology experts and 2 Patent examiners. The digital library will include all details in digital format about international patent classification, traditional research classification, Ayurveda terminology, concepts, definitions, classical formulations, doses, disease conditions and references to documents25. APPLICATIONS: A new Tool for Lead Discovery, reverse pharmacognosy aims to find new biological targets for natural compounds by virtual or real screening and identifying natural resources that contain the active molecules. It has been studied on -viniferin, an active ingredient for cosmetic development26.

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CONCLUSION: India has moved forwards in advocating global usefulness of Ayurveda in the scenario of health care through global net works. As a result many foreign countries have began looking at India for understanding Ayurveda and incorporating it through education, research and practice to meet the overwhelming desire of consumers to access Complementary & Alternative Medicine. Indian Missions in U.S.A., U.K., Russia, Germany, Hungary, and South Africa have played an effective role in channeling the information of Ayurveda and opening up new opportunities for the spread of Indian Medicine in to foreign institutions and the general public awareness building about Ayurveda in the foreign countries has been identified as an important thrust area. So in such an arena reverse pharmacognosy, by making use of it virtual screening tool and important databases can play important role in reducing the time and wealth. It can accelerate the drug discovery to a considerable extent. REFERENCES: 1. D.M. Eisenberg, R.C. Kessler, C.Foster, F.E. Norlock, D.R. Calkins and T.L. Delbanco, Unconventional medicine in the United States Prevalence, costs and patterns of use, N. E. J. M., 328, 246-252 (1993) 2. P. Tollman, P. Guy, J. Altshuler, A. Flanagan and M. Steiner, A revolution in R & D: How genomics and genetics are transforming the biopharmaceuticals industry, The Boston Consulting Group, Boston, MA, USA, (2001) 3. B. Patwardhan and M. Hooper, Ayurveda and future drug development, Int. J. Alternative Complement. Med., 10, 911 (1992) 4. R. Lahana, How many leads from HTS?, Drug Discovery Today, 4(10), 447-448 (1999) 5. P.L. Myers, Will combinatorial chemistry deliver real medicines?, Current Opinions on Biotechnology, 8(6), 701-707 (1997) 6. R. Anton, Plantes Therapeutiques, Lavoisier, Cachan, France, (1999) 7. G. Massiot, How far can one go in the field of structural elucidation of natural products?, J. Ethnopharmacology, 32(1-3),103-110 (1991) 8. P. Tiew, J.R. Loser, U. Kokpol, W. Chavasiri and K. Hostettmann, Antifunagal, antioxidant and larvicidal activities of compounds isolated from the heartwood of Mansonia gagei, Phytother. Res., 17(2), 190-193 (2003) 9. Josang, H.E. Bitar, V.C. Pham and T. Sevenet, Daphcalycine, a novel heptacycle fused ring system alkaloid obtained from Daphniphyllum Calycinum, J. Org. Chem., 68(2), 300-304 (2003) 10. X. Yan, J. Zhou and Z. Xu, Concept Design of Computer-aided study on tradional Chinese drugs, J. Chem. Inf. Compt. Sci., 39(1), 86-89 (1999) 11. P. Bernard, T. Scior, B. Didier, M. Hibert and J.Y. Berthon, Ethnopharmacology and bioinformatics combination for lead discovery: Application to phospholipase A2 inhibitors, Phytochemistry, 58(6), 865-874 (2001) 12. B. Natarajan, B.S. Paulsen and P. Pushpangadan, An Ethnopharmacological Study from the Coimbatore District, Tamil Nadu, India: Traditional Knowledge Compared With Modern Biological Science, Pharmaceutical Biology, 37(5), 378390 (1999) 13. M.T.H. Khan and A. Ather, Lead Molecules from Natural Products: Discovery and New Trends, Elsevier, (2), 1-5 (2006) 14. C.K. Kokate, A.P. Purohit and S.B. Gokhle, Analytical Pharmacognosy, Pharmacognosy, (15), 123-130 (2002) 15. S. Zschocke, I. Klaiber, R. Bauer and B. Vogler, HPLC-coupled spectroscopic techniques (UV, MS, NMR) for the structure elucidation of phthalides in Ligusticum chuanxiong, Mol. Divers, 9(13), 33-39 (2005) 16. M. Ye, Y. Yan and D.A. Guo, Characterization of phenolic compounds in the Chinese herbal drug Tu-Si-Zi by liquid chromatography coupled to electrospray ionization mass spectrometry, Rapid Commun. Mass Spectrom., 19(11), 1469-1484 (2005) 17. Q.T. Do and P. Bernard, Pharmacognosy and Reverse Pharmacognosy: a new concept for accelerating natural drug discovery, I. Drugs., 7(11), 1017- 1027 (2004) 18. Y.C. Martin, M.G. Bures, E.A. Danaher, J. De Lazzer and I. Lico, A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists, J. Comput. Aided. Mol., 7(1), 83- 102 (1993) 19. N. Baurin, E. Vangrevelinghe, L. Morin-Allory, J.Y. Merour, P. Renard, M. Payard, G. Guillaumet, C. Marot, 3D-SAR CoFA study on imidazolinergic I2 ligands : A significant model through a combined exploration of structural diversity and methodology, J. Med. Chem., 43(6), 1109-1122 (2000)

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