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 a Interdisciplinary School of Health Sciences, University of Pune, Pune 411 007, India b Kasturba 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 discoveries resulted from serendipity based on poisonous sources and not really from traditional medicines. The mass screening of plants in the search for new leads or drugs is vastly expensive and inefficient, but traditional knowledge offered better leads. It is estimated that over hundred new natural product-based leads are in clinical development 1 . About 60% of anticancer and 75% of anti-infective drugs approved from 1981-2002 could be traced to natural origins 2 . It would be cheaper and perhaps more productive to re-examine plant remedies described in ancient texts 3 . Many active compounds from traditional medicine sources could serve as good scaffolds for rational drug design. Combinatorial chemistry approaches based on natural product scaffolds are being used to create screening libraries that closely resemble drug-like compounds 4 . Most of these compounds are part of routinely used traditional medicines and hence their tolerance and safety are relatively better known than any other chemical entities that are new for human use 5 . Thus, traditional medicine based bioprospecting offers unmatched structural variety as promising new leads 6 . Large numbers of promising lead molecules have come out of Ayurvedic experiential base including Rauwolfia alkaloids for hypertension, Psoralens in Vitiligo, Holarrhena alkaloids in Amoebiasis, Guggulsterons as hypolipidemic agents, Mucuna pruriens for Parkinson’s disease, Piperidines as bioavailability enhancers, Baccosides in mental retention, Picrosides in hepatic protection, Phyllanthins as antivirals, Curcumines in inflammation, Withanolides, and many other steroidal lactones and glycosides as immunomodulators 7 . There are growing incidences where the old molecules are finding new applications through better understanding of traditional knowledge and clinical observations. For instance, forskolin an alkaloid isolated by Hoechst and coleonol by Central Drug research Institute (CDRI), CSIR, Lucknow a few decades ago from Coleus forskohlii 8 and phytochemicals from Stephania glabra, which were shelved for a considerable time are now being rediscovered as adenylate cylase and nitric oxide activators, which may help in preventing conditions including obesity and atherosclerosis 9 . Antimicrobial berberine alkaloids are now being rediscovered as novel cholesterol-lowering drugs working through different mechanism than statins 10 . Potent anti microbial 11-13 antirheumatic and cyclooxygenase inhibitory activities of phenolics, catechols and flavonoids from an important Ayurvedic plant _________ *Correspondent author E-mail: bhushan@unipune.ernet.in