1. New Drug Discovery From Medicinal Plants/ Natural Products Dabur Research Foundation, Sahibabad

2. Ancient Egyptian, Chinese, and Indian Literature Plant-based remedies and preventives as a major part of treatments Out of a total of 520 new drugs approved in last two decades: 30 were new Natural Products and 127 were chemically modified Natural Products Natural Products as a part of Traditional Medicinal System

3. Prominent Plant Based Drugs of Last century  Quinine, anti-malarial drug, from the bark of Cinchona sp.  Morphine, analgesic, from the opium poppy  Digoxin, for heart disorders, from Digitalis purpurea  Reserpine, Antihypertensive agent, from Rauwolfia serpentina  Ephedrine, anti-asthma agent, from Ephredra sinica  Tubocurarine, muscle relaxant, from Chondrodendron and Curarea species

4. Natural Products as Source of Lead Compounds Bio-diversity Novel Molecular structures Advances in Chemistry and Biology  Radical opportunities in New Drug Discovery  Molecular components of Disease Process as Drug Targets  High Throughput Chemistry & High Throughput Screening  Increasing speed of Drug Discovery Process ?

5. “whether the previously most successful source of drugs (i.e. Natural Products) has any place in modern drug discovery?”

6. Approaches for New Drug Discovery  The Traditional Approach Trial and error based on reports from different cultures and systems of medicine. e.g.Morphine, Quinine and Ephedrine  The Empirical Approach Understandings of a relevant physiological process. Often develops a therapeutic agent from a naturally occuring lead molecule. e.g.Tubocurarine and other muscle relaxants, Propranolol and other β-adrenoceptors antagonists,  The Molecular Approach Availability or understanding of a molecular target for the medicinal agent. Majority of drug discovery is currently based on the Molecular Approach.

7. The Molecular Approach Of Drug Discovery.Rational Drug Design : Based on Computer Aided Techniques.Antisense Approach: Manipulation of Genetic Targets 4Pragmatic Approach: Random Screening of chemical diversity

8. Sources of compoundsTherapeutic Targets Chemical Libraries Historical Compound Collection Natural Product Libraries Combinatorial Libraries Traditional medicinal uses of Natural Products Impirical understanding of Physiology Molecular cloning of receptors and signalling molecules Rational Synthesis Antisense Oligonucleotides Drug Discovery Screening Assays Lead Optimization Drug Development Sources and Approaches for Drug Discovery

9. Redesigning Drug Discovery: Natural Products in High Throughput Era Conventional Bioassays 10,000 /yr High Throughput Screening 100,000 /day ê Combinatorial Chemistry Peptides and Oligonucleotide libraries Small drug-like molecules ê Natural Product Libraries Greater chemical/ Structural Diversity Natural Products are relatively smaller (>1000Da)

10. B: Biological; N: Natural Product, ND: Derived from NP, semisynthetic; S*: Total synthetic; S = semisynthetic NM: Natural Product Mimic; V: vaccine Source: J.Nat.Pr.; 66(7); 2003.

11. Around 52% of the Novel molecules are either Natural Products or Natural Product derivatives 60 - 80% of Anti-Bacterial, and Anti- Cancer drugs are derived from Natural Products -Cragg et al.; J. Nat.Pr. 60(3)

12. M any pharmaceutical companies deemphasized natural product research in favor of high- throughput screening of mass-produced combinatorial libraries *The expectation was rich rewards in terms of multiplicity of novel drugs and resultant revenue windfalls Early 90s Beyond Yr. 2000 The number of NCEs hit the 20 year low ( Only 37 in 2001) FDA received only 16 NDAs in 2001, as compared to 24 in 2000. Need to emphasize on Natural Products research in the search for new therapeutic molecules

13. Natural Products as Sources of New drugs: A Review Natural Product Sources: Plants, Microorganisms, Animals, Marine organisms Molecules with the broadest range of therapeutic application have mostly been obtained from the plant kingdom Microorganisms: “The Golden Age of ANTIBIOTICS”  Anti-bacterial agents from Penicillium species  Immunosuppressants: Cyclosporins & Rapamycin, from Streptomyces sp.  Cholesterol lowering agents: Mevastatin & Lovastatin, from Penicillium sp.  Anthelmintics and antiparasitic drugs, such as the ivermectins, from Streptomyces

14. Oceans and Marine organisms as a vast resource for new therapeutic agents  Pseudopterosins, with significant analgesic and anti-inflammatory properties, from the Caribbean gorgonian Pseudopterogorgia elisabethae  Manoalide, an anti-inflammatory agent, from the sponge Luffarriella variabilis  Ziconotide and other new painkillers derived from peptides from cone snail venom Natural Products as Sources of New drugs…... Several key anti-cancer agents have been produced from natural sources  Vinblastine & vincristine from Madagascar periwinkle, Catharanthus rosesus  Etoposide and teniposide : Semi-synthetic derivatives of Epipodophyllotoxin  Taxol: From the bark of Taxus brevifolia in the northwestern United States

16. Natural Products: Lead for semisynthetic/synthetic modification Diosgenin (Dioscorea sp.) Anabolic steroids, Anti- inflammatory, Oral Contraceptives Morphine (Papaver somniferum) Levophenol, Pentazocine Ephedrine & Pseudoephedrine: Prepared commercially by total synthesis Analogs of a lead molecule may exhibit unexpected biological activity, and then can be modified synthetically even further. e.g. Mepiridine (pethidine) was found to have analgesic activity, which was discovered during screening of a series of compounds intended as anticholinergic agents based on the plant derived alkaloid, atropine. Structural modification of meperidine led to haloperidol series of neuroleptics.

17. Anti-cancer alkaloid Vinorelbine: Semisynthetic Natural Analog with high therapeutic activity. Derived from alkaloids of Vinca rosea in mid 90s. Highly potent in Breast cancers, Testicular cancers, Epithelial ovarian cancers, and Non-small cell lung cancers.

19. The Indian Scenario: Ayurveda in 21 st Century Natural Products (Plants, Minerals, Animal) : Principle Tools of Traditional Healthcare System

20. “Ayurveda” The Science of Life Traditional Medical Paradigms Sophisticated Helathcare Systems Channelizing Ancient Knowledge for Modern Approach to Drug Discovery Ethnopharmacological Approach Study on Drug Actions; based on Cultural or Traditional use Multi-target guided Drug Discovery

21. Future Prospects: Will the Natural Products be still relevant in Drug Discovery for Future? *Frequent Isolation of Known Molecules *Length of Time Required for Characterization *Generation of Analogues from Complex Chemical Templates 4Growing Advancement in the field of Chemistry & Biology 4Identification of Proteins associated with onset of Diseases 4Molecular targets for Screening: High Throughput tools Speeding up the Drug Discovery

22. Conclusions  Linking of Indigenous Knowledge to Modern Research Activities : More Effective Rate of Drug Discovery  Investigating Traditional Medicines with modern theories and Techniques: Absorbing new ideas and concepts from Traditional systems  Tapping the world’s Biodiversity for new Biological Activity  Natural Products made more User Friendly, i.e. reliably and consistently supplied