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Natural Products Drug Discovery: Accelerating the Clinical Candidate Development Using Reverse Pharmacology Approaches

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Natural Products Drug Discovery: Accelerating the Clinical Candidate Development Using Reverse Pharmacology Approaches Indian Journal of Experimental Biology Vol. 48, March 2010, pp. 220-227 Review Article Natural products drug discovery: Accelerating the clinical candidate development using reverse pharmacology approaches Bhushan Patwardhan a* & Ashok D B Vaidya b aInterdisciplinary School of Health Sciences, University of Pune, Pune 411 007, India bKasturba Health Society Medical Research Center, Vile Parle, Mumbai 400 056, India The pharmaceutical industry is facing serious challenges as the drug discovery process is becoming extremely expensive, riskier and critically inefficient. A significant shift from single to multi targeted drugs especially for polygenic syndromes is being witnessed. Strategic options based on natural product drug discovery, ethnopharmacology and traditional medicines are re-emerging to offer good base as an attractive discovery engine. Approaches based on reverse pharmacology may offer efficient development platforms for herbal formulations. Relevant case studies from India and other countries where such approaches have expedited the drug discovery and development process by reducing time and economizing investments with better safety are discussed. Keywords : Ayurveda, Ethnopharmacology, Herbal drugs, Natural products, Reverse pharmacology, Traditional medicine History of medicine revels that most of early Large numbers of promising lead molecules have discoveries resulted from serendipity based on come out of Ayurvedic experiential base including poisonous sources and not really from traditional Rauwolfia alkaloids for hypertension, Psoralens in medicines. The mass screening of plants in the search Vitiligo, Holarrhena alkaloids in Amoebiasis, for new leads or drugs is vastly expensive and Guggulsterons as hypolipidemic agents, Mucuna inefficient, but traditional knowledge offered better pruriens for Parkinson’s disease, Piperidines as leads. It is estimated that over hundred new natural bioavailability enhancers, Baccosides in mental product-based leads are in clinical development 1. retention, Picrosides in hepatic protection, About 60% of anticancer and 75% of anti-infective Phyllanthins as antivirals, Curcumines in drugs approved from 1981-2002 could be traced to inflammation, Withanolides, and many other steroidal natural origins 2. It would be cheaper and perhaps lactones and glycosides as immunomodulators 7. more productive to re-examine plant remedies There are growing incidences where the old described in ancient texts 3. molecules are finding new applications through better understanding of traditional knowledge and clinical Many active compounds from traditional medicine observations. For instance, forskolin an alkaloid sources could serve as good scaffolds for rational isolated by Hoechst and coleonol by Central Drug drug design. Combinatorial chemistry approaches research Institute (CDRI), CSIR, Lucknow a few based on natural product scaffolds are being used decades ago from Coleus forskohlii 8 and to create screening libraries that closely resemble 4 phytochemicals from Stephania glabra , which were drug-like compounds . Most of these compounds are shelved for a considerable time are now being part of routinely used traditional medicines and hence rediscovered as adenylate cylase and nitric oxide their tolerance and safety are relatively better known activators, which may help in preventing conditions than any other chemical entities that are new for 9 5 including obesity and atherosclerosis . Antimicrobial human use . Thus, traditional medicine based berberine alkaloids are now being rediscovered as bioprospecting offers unmatched structural variety as 6 novel cholesterol-lowering drugs working through promising new leads . different mechanism than statins 10 . Potent anti 11-13 microbial antirheumatic and cyclooxygenase _________ *Correspondent author inhibitory activities of phenolics, catechols and E-mail: [email protected] flavonoids from an important Ayurvedic plant PATWARDHAN & VAIDYA: REVERSE PHARMACOLOGY IN DRUG DISCOVERY 221 Semecarpus anacardium have been reported as Committee briefings on new anticoagulant promising leads. Small-molecule drugs that can Ximelagatran of Astra Zeneca or Cox II inhibitor regulate TNF-α levels or activity may provide a Vioxx of Pfizer are very indicative of the impasse 22 . cost-effective alternative to protein-based Drug discovery and development process involves therapeutics 14 . Natural products also provide a vast a 10-15 years of investigation period and investments pool of pancreatic lipase inhibitors as potential of the order of US $ 1 to 1.5 billion are not candidates, which can be developed into new drugs uncommon. This extremely complex, technology for treatment of conditions like obesity 15 . A large based and capital-intensive process has resulted in number of promising leads for development of newer ‘target rich lead poor’ performance. Obviously, the antiinflammatory drugs are also available in pharmaceutical companies are looking beyond medicinal plants 16 . conventional drug discovery and development approaches not only to expedite the process, but also Drug discovery: Current scenario to ensure that safer and effective drugs could be The pharmaceutical industry has historically seen launched faster and sustained (Fig. 1). an incredible growth primarily due to the discovery of Over this background the importance of blockbuster drugs with the potential to generate over experiential wisdom and holistic approach is 1 billion US $ sales. However, recent trends indicate intensifying to offer good base as an attractive that this model may no longer lead to high growth discovery engine 5. Natural product drug discovery, rates. The average cost and time of discovering, ethnopharmacology, traditional, complementary and developing and launching a new drug is consistently alternative medicines are re-emerging as new strategic increasing without an expected corresponding options 23 . The World Health Organization’s increase in the number of newer, safer and better Commission on Intellectual Property and Innovation drugs. As compared to the previous years the numbers in Public Health also has duly recognized the promise of New Molecular/ Chemical Entities produced per and role of traditional medicine in drug development company have declined. Moreover, the number of for affordable health solutions 24 . approvals for new drugs has steadily declined from 53 in the year 1996 to 17 in 2007 17 . Clearly, drug Reverse pharmacology discovery is no more a game of chance or just limited Reverse pharmacology is defined as the science of to technology availability today. The strategies that integrating documented clinical experiences and awarded success during the past may not guarantee experiential observations into leads by success in the future 18 . The industry is really facing a transdisciplinary exploratory studies and further major challenge to sustain and grow, which is developing these into drug candidates or formulations resulting in many mergers, acquisitions or closures 19 . through robust preclinical and clinical research 25 . The The situation is progressively deteriorating and traditional knowledge inspired reverse pharmacology analyst predict that worst is yet to come 20 . The global described here relates to reversing the routine market situation and current financial crisis is bound ‘laboratory to clinic’ progress of discovery pipeline to to compound these pressures even to higher intensity. ‘clinics to laboratories’ 26 . In this process ‘safety’ The age of the blockbuster drug seems to be over or remains the most important starting point and the at least in its last days. The usual distinctions drawn efficacy becomes a matter of validation. between breakthrough and me-too drugs may not be Sir Ram Nath Chopra and Gananath Sen laid the very relevant today 21 . Critiques argue that the foundation of reverse pharmacology of medicinal pharmaceutical industry has not been as innovative as plants by pursuing clinically documented effects of it claims to be. Despite very stringent and tedious Ayurvedic drugs 27 . Rauwolfia serpentina Benth, was a regulatory processes the industry has agonizingly major discovery via this approach. Sen and Bose in experienced increased incidences of post approval or 1931 convincingly demonstrated the antihypertensive post marketing withdrawal of new drugs. Increasingly and tranquillizing effects of the plant and also cautious regulatory processes are adding more risk observed unique side effects such as depression, extra and years for the pharmaceutical companies. The pyramidal syndrome, gynecomastia and peptic ulcer 28 . United States Food and Drug Administration This effort led to a watershed for new antidepressants, (US FDA)’s Drug Watch and Drug Advisory anti Parkinson’s drugs and prolactin–reducing drugs 29 . 222 INDIAN J EXP BIOL, MARCH 2010 Fig. 1—Drug discovery and development: Conventional versus reverse pharmacology. (a) Conventional: Time, investment and risk intensive; (b) Traditional medicine inspired reverse pharmacology: Faster, economical and safe. Reserpine, an anti-hypertensive alkaloid from R. inadequate industry involvement during the serpentina became available for the treatment of development cycle. hyper-tension by Ciba-Geigy. CSIR, under the national network project known as Concept of reverse pharmacology was practiced for New Millennium Indian Technology Leadership several years at Ciba-Geigy and Podar Ayurveda Initiative (NMITLI) attempted to bridge this gap by Hospital, Mumbai. Some
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