Introduction To Drug Discovery

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an introduction to drug discovery

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  • Introduction To Drug Discovery

    1. 1. HERBAL AND DRUG DESIGN TECHNOLOGY Selma Siyavudeen
    2. 2. (IUPAC Recommendations 1997) <ul><li>Drug design Drug design includes not only ligand design, but also pharmacokinetics and toxicity, which are mostly beyond the possibilities of structure- and/or computer-aided design. </li></ul><ul><li>Drug design is most often used instead of the correct term &quot;Ligand Design”. </li></ul>
    3. 3. The process of drug discovery <ul><li>Primary requirement - Target identification </li></ul><ul><li>The disease against which a drug has to be developed . </li></ul><ul><li>New drug research starts with an understanding of how the body functions, both normally and abnormally, at its most basic levels. </li></ul>
    4. 4. Drug discovery / design - steps IDENTIFICATION OPTIMISATION DEVELOPMENT FINDING A LEAD COMPOUND / NCE QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS, ASSAYS – in vitro and in vivo PHARMACOKINETIC STUDIES TOXICOLOGY TESTING FORMULATION DEVELOPMENT CLINICAL TRIALS REGULATORY APPROVAL LEAD
    5. 5. Drug design (ligand design) <ul><li>STEP 1 </li></ul><ul><li> LEAD IDENTIFICATION </li></ul><ul><li>Find a lead compound /NCE (New Chemical Entity) </li></ul><ul><li>This is usually a molecule with demonstrable but weak activity of the desired type </li></ul><ul><li>. </li></ul>
    6. 6. sources of lead compounds <ul><li>Random screening - plants, animal, microbial & synthetic sources </li></ul><ul><li>Observed side effects of known drugs </li></ul><ul><li>eg. oral antidiabetic agent tolbutamide was discovered by the careful molecular modification of a sulfa drug which showed lowering of blood glucose as a side effect.(Grunwald 1970) . </li></ul>
    7. 7. <ul><li>Natural products of known pharmacological properties </li></ul><ul><li> eg. the structure of the natural anticoagulant, bishydroxycoumarin, led to the synthesis of a distant analogue the widely used anticoagulant drug warfarin </li></ul><ul><li>structure of natural body substances . </li></ul><ul><li>enzyme inhibitors are often designed from the structure of substrates. </li></ul><ul><li> eg. The monoamine oxidase inhibitor pargyline is an analogue of the substrate,benzyl amine.(Martin et al,1975) </li></ul>
    8. 8. <ul><li>Insilico approach/computer assisted drug design (CADD) </li></ul><ul><li>Based on ligand receptor binding </li></ul><ul><li>Ligand based or receptor based designs </li></ul>
    9. 9. An Example of CADD: Carbonic anhydrase <ul><li>CO 2 +H 2 O HCO 3 + H + </li></ul><ul><li>the hydration of some aldehydes and ketones, and the hydrolysis of alkyl and aryl esters. </li></ul><ul><li>Inhibitors include aromatic and heterocyclic sulfonamides </li></ul><ul><li>(MTS [(4S-trans)-4-(methylamino)-5,6-dihydro-6-methyl-4H-thieno (2,3-B)thiopyran-2-sulfonamide-7,7-dioxide </li></ul>
    10. 10. <ul><li>engage in a greater number of favorable interactions within the large carbonic anhydrase active site than can the smaller arylsulfonamides. </li></ul>
    11. 11. CADD Advantages & Limitations <ul><li>flexible, faster docking techniques, virtual screening and library design. </li></ul><ul><li>identifying potential drugs than may be considerably different from existing drugs. </li></ul><ul><li>reduced reagent storage and handling of large libraries </li></ul><ul><li>optimum fit in a target site does not guarantee that the desired activity of the drug will be enhanced or that undesired side effects will be diminished. </li></ul>
    12. 12. STEP II LEAD OPTIMISATION <ul><li> synthesize and test an exploratory series if analogues of the lead. </li></ul>
    13. 13. Synthesis of homologues and analogues from a prototype <ul><li>Method of variaton </li></ul><ul><li> Tool for design of new drugs in a rational fashion, having more desirable properties and advantages than the prototype. </li></ul><ul><li>Variation through disjunction or conjunction </li></ul><ul><li>Objectives Include the design of agents with improved </li></ul><ul><li>Potency </li></ul><ul><li>Specificity </li></ul><ul><li>Duration of action </li></ul><ul><li>Ease of administration and handling </li></ul><ul><li>Stability </li></ul><ul><li>Cost of Production </li></ul>
    14. 14. design of variants <ul><li>Familiarize thoroughly with the prototype </li></ul><ul><li>From the molecular structure information can be drawn about </li></ul><ul><li>The nature of chief chemical classes to which the product belongs as determined by the main stem nuclei or the hydrocarbon skeleton from which it derives its name </li></ul><ul><li>The nature and number of various functional groups their positions and their proximity with respect to one another. </li></ul><ul><li>The various possible degrees of rotations and extension of the structure in to various possible configurations. </li></ul><ul><li>The likelihood of steric hindrance between various portions of the molecule in different configurations in space </li></ul>
    15. 15. QSAR <ul><li>Formulate a preliminary quantitative structure- activity relationship (QSAR) and designs further analogues to test and expand the relationship. </li></ul><ul><li>attempt to correlate structural or property descriptors of compounds with activities </li></ul>
    16. 16. QSAR <ul><li>parameters to account for </li></ul><ul><li>hydrophobicity, </li></ul><ul><li>topology, </li></ul><ul><li>electronic properties, </li></ul><ul><li>steric effects, </li></ul><ul><li>determined </li></ul><ul><li>Empirically </li></ul><ul><li>statistical analysis, </li></ul><ul><li>computational methods. </li></ul><ul><li>chemical measurements and biological assays. </li></ul>
    17. 17. Step iii Lead Development <ul><li>Preclinical testing </li></ul><ul><li>Clinical trials </li></ul><ul><li>Pharmacovigilance </li></ul><ul><li>Toxicology </li></ul><ul><li>Pharmacokinetics/ADME </li></ul><ul><li>Preformulation </li></ul><ul><li>Formulation </li></ul><ul><li>Phase I,ii,iii,iv </li></ul>
    18. 18. Animal pharmacokinetic studies <ul><li>ADME Studies using radioactive versions of NCE </li></ul><ul><li>Absorption </li></ul><ul><li>Distribution </li></ul><ul><li>Metabolism </li></ul><ul><li>Excretion </li></ul>
    19. 19. <ul><li>Safety pharmacology </li></ul><ul><li>Genotoxicity – gene mutations </li></ul><ul><li>Acute toxicity testing </li></ul><ul><li>Repeat toxicity testing </li></ul><ul><li>Reproductive toxicology </li></ul><ul><li>carcinogenicity </li></ul>Toxicity testing
    20. 20. Formulation development <ul><li>Preformulation involves </li></ul><ul><li>Solubility determination </li></ul><ul><li>pKa determination </li></ul><ul><li>Partition coefficient </li></ul><ul><li>Chemical stability profile </li></ul><ul><li>Particle size, shape and surface area </li></ul><ul><li>Formulations should be </li></ul><ul><li>Stable </li></ul><ul><li>Easy to administer </li></ul><ul><li>Easy and economic to manufacture </li></ul><ul><li>East to transport and store </li></ul>
    21. 21. Clinical trials
    22. 22. REVOLUTIONS IN DRUG DESIGN technology <ul><li>Advances in molecular biology , </li></ul><ul><li>Genomics </li></ul><ul><li>Microarray technology </li></ul><ul><li>Development of high throughput screening </li></ul><ul><li>Advances in computer assisted molecular design </li></ul><ul><li>(CADD & CASE) </li></ul>
    23. 23. Advances in molecular biology-newer targets for drugs <ul><li>Identification of physiologically relevent molecular targets </li></ul><ul><li>determination and implementation of appropriate screening assays </li></ul><ul><li>Development of drugs with new pharmacological mode of action </li></ul><ul><li>HMG Co A reductase inhibitors - new drug target for reducing cholesterol levels </li></ul>
    24. 24. Advances in recombinant DNA technology - biopharmaceuticals <ul><li>Blood products </li></ul><ul><li>Clotting factors </li></ul><ul><li>Anticoagulants </li></ul><ul><li>Thrombolytic agents </li></ul><ul><li>Recombinant vaccines </li></ul><ul><li>Haemopoetic growth factors </li></ul><ul><li>Interferons </li></ul><ul><li>Interleukins </li></ul><ul><li>Monoclonal antibody based products </li></ul>
    25. 26. Advances in genomics & Microarray Technology Drug development Tracking disease progression Disease risk assessment Genotyping Drug development Drug response Tracking disease progression Therapy development Drug mechanism of action Applications Detect mutations/polymorphisms Analysis of gene expression levels Breif description Mutation/polymorphism analysis Expression analysis Microarray type
    26. 27. Herbal drug design <ul><li>Herbal drugs – drug discovery from plants </li></ul><ul><li>Involves a multidisciplinary approach </li></ul><ul><li>Combining </li></ul><ul><li>Botanical </li></ul><ul><li>Ethnobotanical </li></ul><ul><li>Phytochemical </li></ul><ul><li>Biological techniques </li></ul>
    27. 28. Historical perspective anticancer Vinca rosea vincristine anticancer Vinca rosea vincaleukoblastine Hypotensive,tranquilizer rauwolfia reserpine foxflove digitoxin cocaine cinchona quinine opium morphine
    28. 29. What should be the approach? <ul><li>Collection of plants based on ethnopharmacological information or random screening </li></ul><ul><li>Standardise the extraction procedures </li></ul><ul><li>Subject extract to pharmacologically relevant assays </li></ul><ul><li>Isolation and characterisation of the active compounds through bioassay directed fractionation </li></ul><ul><li>Peridic reexamination of plant collections with new screening systems </li></ul>
    29. 30. Fractionation of tumor inhibitory extract <ul><li>powdered leaves ( 1.5kg ) (Vernonia hymenolepis) </li></ul><ul><li>Conc.chloroform extract (87.0 gm ) </li></ul><ul><li>10% aq.methanol interfacial solid petroleum ether extract (51.0gm ) (10.6gm ) extract (23.8gm) </li></ul><ul><li>silica gel chromatography </li></ul><ul><li>solvent 15% acetone in chloroform </li></ul><ul><li>Vernomenin (6.5gm), </li></ul><ul><li>Vernolepin ( 5.5gm) </li></ul>
    30. 31. Recent discoveries Galanthus Woronowii Losinsk . Alzheimer”s disease Galanthamine Artemesia annua L. Antimalarial drug Arteether Taxus brevifolia Nutt. Camptotheca acuminata Decne. Catharanthus roseus G.Don plant Anticancer agents properties Paclitaxel Camptothecin Vinflunine Drug
    31. 32. Papaver somniferum L. Pain medication Morphine 6-gluconoride Calophyllum lanigerum var. austrocoriaceum Atropa belladona L. Anti HIV drugs antiretroviral and anti mycobacterial agent , n on-nucleoside reverse transcriptase inhibitor of type 1 HIV Effective against AZT resistant strains of HIV Chronic obstructive pulmonary disease inhaled bronchodialator Calanolide A Tiotropium
    32. 33. NCE s from India Coleus forskohlii Briq. Dysoxylum binectariferum Hook. Potent adenylate cyclase activator Semisynthetic derivative is approved for treatment of glaucoma tyrosine kinase activity and potent growth inhibitory activity against breast and lung carcinoma cell lines. Forskolin Flavopiridol
    33. 34. Commiphora mukul (Stocks)Engl. Lowers serum LDL and triglyceride levels highly efficacious antagonist of FXR (farnesoid X receptor) Guggulsterone, [4,17,(20)-pregnadiene-3,16-dione]
    34. 35. Herbal product development <ul><li>Herbal products are usually whole herbs, their formulations or extracts consisting of several bioactive compounds. </li></ul><ul><li>a paradigm shift from single-target drugs to multi-target drugs . </li></ul><ul><li>Multi-target approaches are directed toward activation of defence, protective repair mechanisms of the body rather than destruction of the damage-causing agent. </li></ul><ul><li>The concept of multi-targeted therapy exists in traditional medical treatments that employ multi-component extracts of natural products. </li></ul>
    35. 36. <ul><li>Standardisation of herbal products is difficult </li></ul><ul><li>difficult to precisely predict the molecular targets, mechanism of action and side effects </li></ul><ul><li>for scientifically validated and standardized herbal product there is a need for better understanding of the molecular mechanisms underlying their biological activity. </li></ul><ul><li>DNA microarrays provide a suitable high-throughput platform for research and development of drugs from natural products </li></ul><ul><li>through gene expression studies </li></ul><ul><li>allow rapid and detailed analysis of thousands of transcripts, providing a revolutionary approach to the investigation of gene expression. </li></ul>
    36. 37. DNA Microarray - applications
    37. 38. Microarray-based gene expression analysis of multi-component mixtures.
    38. 39. <ul><li>In pharmacogenomics </li></ul><ul><li>identification of genes involved in conferring drug sensitivity or resistance. </li></ul><ul><li>for prediction of potential side-effects of the herbal drug during preclinical activity and safety studies (toxicogenomics) </li></ul>
    39. 40. <ul><li>In pharmacognosy for correct botanical identification and authentication of crude plant materials as part of standardization and quality control </li></ul><ul><li>microarrays applied for the DNA sequence-based identification of medicinal plants using species specific probes </li></ul>
    40. 41. Conclusion <ul><li>Rich biodiversity </li></ul><ul><li>Huge prospects for plant based drug discovery and validation </li></ul>
    41. 42. <ul><li>THANK YOU </li></ul>

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