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Drug discovery challenges and different discovery approaches

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Drug discovery challenges and different discovery approaches

  1. 1. Drug Discovery Challenges and Different Discovery ApproachesPresentation by:- Hitesh SoniCONFIDENTIAL
  2. 2. Drug Discovery Challenges WithdrawnCONFIDENTIAL
  3. 3. Drug Discovery ChallengesCONFIDENTIAL
  4. 4. Drug Discovery ChallengesCONFIDENTIAL
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  14. 14. Different Discovery ApprochesNatural products as a source of Transient binding drugs Multitarget drugsnew drug leads and new drugsCONFIDENTIAL
  15. 15. Drugs or Drug lead from NatureNature to lab to clinicNatural compounds again become central playerHistoryDigitalis(1785)-William Withering-small molecule digoxin- Lead to Understanding thebiochemistry and biology of Na-K-ATPase pumpMorphine(1806)- Freidrich Serturner-Pain- Enabled to understand the Opiate receptorsubtypes and endorphine-enkephalin pathwaysAspirin (1897)- Felix Hoffmann- Salicylic acid from Willow bark-Synthesis of Aspirin fromSA- Decided the test battery of NSAIDs Like COX-2 inhibitors, Synthetic drugs, inherentsafety issuesPenicillin from mold (1928)- Alexander FlemingUnderstand the Antibiotics and role of M.O.Mid-1900s, era of Synthetic Sulfa drugs– Allergy, Resistance20 th century- Natural Products- Endogenous chemicals- Steroids,PGs, Peptide hormones-Played a major role in drug discovery20 th century- Redefined enzymology and Redefined receptor pharmacologyCONFIDENTIAL
  16. 16. Drugs or Drug lead from Nature Biochemical assay arena- Tools for measuring the potency and Selectivity HTS (Made natural product drug discovery impractical) Accelerated the rate of new drug discovery Shift from functional assays to artificial assays that measured molecular InteractionCONFIDENTIAL
  17. 17. Drugs or Drug lead from Nature Modern and advanced technologies to predict the drug interactions, New technologies in drug discovery, like HTS, sensitive bioassays Failure in drug development/ low success rate even though increased Drug discovery expenditure What’s wrong????????????CONFIDENTIAL
  18. 18. Drugs or Drug lead from Nature Revisit the nature using approaches, Lead from nature Functional biological assay Whole cell cytotoxicity assay Classical Pharmacological approach and animal model Extrapolation from Mouse-Rat-Dog-Monkey- Human??? Humanized animal models- Genetic approachCONFIDENTIAL
  19. 19. Drugs or Drug lead from Nature Examples Amphotericin B- S. nodosus- Gold standard for systemic fungal Infection- Synthesis Rapamycin (Sirolimus)- S. hygroscopicus- Antifungal but toxic, Revisited due to immunosuppressive properties. Rapamycin-eluting stents-approved By FDA 2003, 2007-semisynthetic analogue-Temsirolimus-approved by FDA for advanced renal cell carcinoma, Synthesis Taxol (Paclitaxel) Bark of pacific yew tree Taxus brevifolia. Taxol structure discovered in 1971. Launched in 1992 for refractory ovarian cancer. Paclitaxel stents approved by FDA,2004CONFIDENTIAL
  20. 20. Drugs or Drug lead from Natural source Path , not easy Synthesis- very difficult due complexity but not impossible Screening by modern technologies- possible Evaluation in refined animal modelsCONFIDENTIAL
  21. 21. Transient binding drugs Mind set- Weak binders are undesired and no benefit. Drug design towards highest possible binder to given target (receptor). Fact- biological interactions are weak or transient (dissociation Constant: Kd>µM) Transient Interactions Exerts biological effects by, Parallel binding Simultaneous binding between multiple sites on biological molecules Polyvalent interactions- much strong than monovalent Example Dynamic binding of cells to cells, such as white blood cells rolling over the surface of endothelial cells during inflammation. Simultaneous transient binding of selectin molecules on the surface of one type of cell with sialyl Lewis X structures on the other cell mediates this interaction. These interactions lead to penetration of white blood cells at the inflammation site. Serial Binding Repeated weak binding events Activation of T cells during immune recognition. Signal transduction seems to be as a result of repeated serial binding (knocking on receptor) between peptide–MHC complexes and multiple T cell receptors.CONFIDENTIAL
  22. 22. Transient binding drugs Transient binding drugsWeak binding (SubµM) Transient bindingMonovalent Individual weak binding With many targetsHigh off rates Polyvalent binding (multitarget)Low on rates Multivalent interactions 1+0=1Memantine, which was recently result from simultaneousapproved for the treatment of binding of several sites 1+1=>2Alzheimer’s disease, shows binding to on the same moleculethe NMDA receptor in the mMrange with multiple receptorwith an off-rate of approximately 0.4/s. sites.It is clear that this approach, usingweakly binding drugs with fast off-rates, The antigen-antibody complexcould be a key factor in designing with the immunoglobulin Meffective ion-channel blockers, and that (IgM) is an illustrative example ofthis principle can apply to a number of the natural existence of aneurological and other targets. multivalent assembly that can be composed of individual weakFoser et al. and Bailon et al. showed that binding sites.PEGylated interferons for treatment ofchronic hepatitis C showed decreased Anticanceraffinities (near to mM) compared to the Antibiotics to minimize drugparent interferon, because of partly lower resistanceon rates.CONFIDENTIALFaster kinetic
  23. 23. Transient binding drugsWeakly binding drugs/weak biological interactions are not studied because of difficulties inscreening or analyzing them; that is, ‘if you cannot see them, they do not exist.’Fortunately, there are a number of emerging techniques to study and screen transientinteractions.Specificity = desired interaction vs. nondesired interaction. Ratio may be higher for weakbinders.Kd= 1 µM- consired as nonspecific most of the times 1 µM is sufficient to fill the half of thereceptor sitesCONFIDENTIAL
  24. 24. Transient binding drugs, BenefitsExamples of drugs that can be considered as transiently binding are alcohol (ethanol) and nonsteroidal anti-inflammatorydrugs (NSAIDs), such as aspirin, naproxen and ibuprofen. In a complex way, alcohol affects synapses of the central nervoussystem (CNS) and can be considered a transient binder, because of its perceived low affinity for different receptors in thebrain where rather high concentrations are needed to produce biological effect.Other examples of weak enzyme inhibitors are valproic acid and butyric acid, which affect histone deacetylases.Transient binding could also be of great value to screen for weak interactions of drug candidates to targets that produce side effects,since these effects can be subtle. Cytochrome P450 (CYP) enzymes are a group of approximately 50 enzymes that metabolize, and arelargely responsible for clearance of, many drug compounds.It may be of interest to study the upregulation of CYP enzymes because of weak interactions of drug substances during a longer period oftime. Negative screening for weak binding to CYP enzymes has potential for selection of drug candidates with minimal CYPinterference.Another important issue in drug discovery is receptor desensitization.It may be situations where weakly binding substances aresufficient to cause signal transduction but not receptor desensitization.CONFIDENTIAL
  25. 25. Multitarget ApproachCONFIDENTIAL
  26. 26. Multitarget ApproachCONFIDENTIAL
  27. 27. Multitarget ApproachComplex conditions, such as cancer, inflammation, depression andcardiovascular diseases, are not caused by a single molecular defect, but arerather the result of a combination of molecular dysfunctions.An illustrative example of a ‘promiscuous’ drug is the anti-cancer agentGleevec (Imatinib Mesylate) which shows promise in treatment of leukemia.Although it was originally designed to hit a particular target, it was soonrealized that this drug was a multiple-target kinase inhibitor. Another illustrative group of drug compounds that show a broad binding spectrum are anti-psychotic agents where many of these bind to a plethora of neuronal receptorsCONFIDENTIAL
  28. 28. Multitarget Approach It is clear that the ‘magic bullet’ strategy to solve complex diseases has not been as successful as anticipated, suggesting instead that a ‘magic shotgun’ strategy may be a viable alternative for a variety of disorders A multi-target drug will frequently be a transient binder, since it can interact with a number of disparate targets. In other words, cross reactivity of the drug should be substantial so that it can theoretically interact with multiple targets for maximum efficiency.CONFIDENTIAL
  29. 29. Multitarget ApproachCONFIDENTIAL
  30. 30. Finally Perhaps most importantly, ‘old fashioned’ drug development might come back. If you want to know the response of a complex system, ‘ask’ the system (by testing drug candidates in complex in vivo tests)! And, although microarray techniques might be useful to follow multi- target drug strategies, in vivo pharmacology (i.e. whole-animal studies) might become important again . Furthermore , advances in genetics leads to more-efficient in vivo testing, better animal models are needed. Better animal models can be achieved by ‘humanizing’ the metabolism and signaling of test animals. Disease target genes and their protein products might be transformed from drug targets to core elements of better animal models in the future.CONFIDENTIAL
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