Natural Products and Drug Discovery

Transcription

1 Natural Products and Drug Discovery

2 Secondary metabolism Building blocks & Phytochemicals Drug discovery 26-Oct-18 2

3 Secondary metabolism: Biochemical reactions derived from primary metabolic pathways used by plants, microorganisms, algae, marine organisms, insects and some animals to accommodate with their environment and/or growth regulation through production of chemicals called secondary metabolites. 26-Oct-18 3

4 These metabolites show biological importance and are targets for pharmaceutical industry. 26-Oct-18 4

5 It is the study of the biochemical pathways leading to the formation of secondary constituents that are used as drugs. The different types of biochemical reactions within the biologic system will lead to sequence of different types of secondary constituents used as drugs (Fig bellow) 26-Oct-18 5

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7 Enzymes and enzymatic reactions involved in the construction of NPs. 26-Oct-18 7

8 - Aldol and Claisen reactions Is a C-C bond formation in base catalyzed chemical reaction through a resonance-stabilized enolate anion. The starting material will be Coenzyme esters such as AcetylCoA. 26-Oct-18 8

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12 - Mannich condensation Reaction Here we have the formation of C-N bond through condensation between and aldehyde/ketone and an amine. 26-Oct-18 12

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14 - β-oxidation of fatty acids Is a catabolic degradation of fatty acids and consequent release of (2C) acetyl-coa in each step catalyzed by multi-step enzymatic reaction 26-Oct-18 14

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16 - Transamination reactions Is an exchange of the amine gp. In an amino acid with a ketoacyl gp. Catalyzed by transaminases. 26-Oct-18 16

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18 The glutamic acid 2-oxoglutaric acid couple provides the usual donor acceptor molecules 26-Oct-18 18

19 - Decarboxylation reaction A degradative reaction ends with the removal of a carbonyl gp. From an amino acid catalyzed by decarboxylases. 26-Oct-18 19

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22 - Other reactions like oxidation-reduction and oxidative coupling reactions also take place catalyzed by oxidases and reductases. 26-Oct-18 22

23 - Glycosylation reactions Addition of a sugar molecule (mostly D-Glucose) to an aglycone moiety catalyzed by glycosidases. The product is a glycoside. (the detailed reaction will be studied with glycosides) 26-Oct-18 23

24 Oxidative degradation of D-Glucose (glycolysis) and formation of building blocks 26-Oct-18 24

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26 Natural Products classes NPs are classified according to their chemical nature as follows:- 26-Oct-18 26

27 Glycosides. Terpenoids. Steroids. Tannins. Phenylpropanoids. Lignans. Alkaloids. Peptides and Proteins. Carbohydrates. Fatty acids and eicosanoids. 26-Oct-18 27

28 The origin of drugs Drug development follows a logical progression from an unmodified natural product (usually extracted from an herb) to a synthetic modification of that natural chemical entity, to a purely synthetic compound apparently showing little relationship to its natural forebears. 26-Oct-18 28

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30 All these previous agents share similar stereochmical features that seems to be essential for their pharmacological actions including:- 26-Oct-18 30

31 1. A flat configuration enabling them to fit a specific receptor site on an enzyme. 2. Acidic and strongly ionized at a physiological ph allowing aqueous solubility to concentrate in plasma and extracellular water. 3. Sufficient lipid solubility to allow them to penetrate biological membranes easily. 26-Oct-18 31

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34 Stages of Drug Development 1.Discovery 2.Product Characterization 3.Formulation, Delivery, Packaging Development 4.Pharmacokinetics And Drug Disposition 5.Preclinical Toxicology Testing 6.Bioanalytical Testing 7.Clinical Trials 26-Oct-18 34

35 The following review will look at key preclinical stages of the drug discovery process, from initial target identification and validation, through assay development, high throughput screening, hit identification, lead optimization and finally the selection of a candidate molecule for clinical development. 26-Oct-18 35

36 Lead molecules oftenly comes from natural sources 26-Oct-18 36

37 Discovery often begins with target identification choosing a biochemical mechanism involved in a disease condition. Drug candidates, discovered in academic and pharmaceutical/biotech research labs, are tested for their interaction with the drug target. 26-Oct-18 37

38 Up to 5,000 to 10,000 molecules for each potential drug candidate are subjected to a rigorous screening process which can include functional genomics and/or proteomics as well as other screening methods. 26-Oct-18 38

39 Once scientists confirm interaction with the drug target, they typically validate that target by checking for activity versus the disease condition for which the drug is being developed. After careful review, one or more lead compounds are chosen. 26-Oct-18 39

40 When the candidate molecule shows promise as a therapeutic agent, it must be characterized the molecule s size, shape, strengths and weaknesses, preferred conditions for maintaining function, toxicity, bioactivity, and bioavailability must be determined. 26-Oct-18 40

41 Early stage pharmacology studies help to characterize the underlying mechanism of action of the compound. 26-Oct-18 41

42 Drug developers must devise a formulation that ensures the proper drug delivery parameters. It is critical to begin looking ahead to clinical trials at this phase of the drug development process. 26-Oct-18 42

43 Drug formulation and delivery may be refined continuously until, and even after, the drug s final approval. Scientists determine the drug s stability in the formulation itself, and for all the parameters involved with storage and shipment, such as heat, light, and time. 26-Oct-18 43

44 The formulation must remain active and sterile; and it must also remain safe (nontoxic) during shelf live. 26-Oct-18 44

45 Pharmacokinetic (PK) or ADME (Absorption/Distribution/Metabolism/Elimination) studies provide useful feedback for formulation scientists. PK studies yield parameters such as AUC (area under the curve), Cmax (maximum concentration of the drug in blood), and Tmax (time at which Cmax is reached). 26-Oct-18 45

46 Later on, this data from animal PK studies is compared to data from early stage clinical trials to check the predictive power of animal models. 26-Oct-18 46

47 Preclinical Toxicology Testing and IND Application 26-Oct-18 47

48 Preclinical testing analyzes the bioactivity, safety, and efficacy of the formulated drug product. 26-Oct-18 48

49 During the preclinical stage of the development process, plans for clinical trials and an Investigative New Drug (IND) application are prepared. Studies taking place during the preclinical stage should be designed to support the clinical studies that will follow. 26-Oct-18 49

50 The main stages of preclinical toxicology testing are: Acute Studies Acute toxicology studies look at the effects of one or more doses administered over a period of up to 24 hours. The goal is to determine toxic dose levels and observe clinical indications of toxicity. 26-Oct-18 50

51 Usually, at least two mammalian species are tested. Data from acute toxicology studies helps to determine doses for repeated dose studies in animals and Phase I studies in humans. 26-Oct-18 51

52 Repeated Dose Studies Depending on the duration of the studies, repeated dose studies may be referred to as subacute, subchronic, or chronic. The specific duration should anticipate the length of the clinical trial that will be conducted on the new drug. Again, two species are typically required. 26-Oct-18 52

53 Genetic Toxicity Studies These studies assess the likelihood that the drug compound is mutagenic or carcinogenic. Procedures such as the Ames test (conducted in bacteria) detect genetic changes. DNA damage is assessed in tests using mammalian cells such as the Mouse Micronucleus Test. The Chromosomal Aberration Test and similar procedures detect damage at the chromosomal level. 26-Oct-18 53

54 Reproductive Toxicity Studies Segment I reproductive toxicology studies look at the effects of the drug on fertility. Segment II and III studies detect effects on embryonic and post-natal development. In general, reproductive toxicological studies must be completed before a drug can be administered to women of child-bearing age. 26-Oct-18 54

55 Carcinogenicity Studies Carcinogenicity studies are usually needed only for drugs intended for chronic or recurring conditions. They are time consuming and expensive, and must be planned for early in the preclinical testing process. 26-Oct-18 55

56 Toxicokinetic Studies These are typically similar in design to PK/ADME studies except that they use much higher dose levels. They examine the effects of toxic doses of the drug and help estimate the clinical margin of safety. There are numerous FDA and ICH guidelines that give a wealth of detail on the different types of preclinical toxicology studies and the appropriate timing for them relative to IND and NDA or BLA filings. See Regulatory/Animal Welfare and at 26-Oct-18 56

57 Bioanalytical Testing 26-Oct-18 57

58 Bioanalytical laboratory work supports most of the other activities in the drug development process. The bioanalytical work is key to proper characterization of the molecule, assay development, developing optimal methods for cell culture or fermentation, determining process yields, and providing quality assurance and quality control for the entire development process. It is also critical for supporting preclinical toxicology/pharmacology testing and clinical trials. 26-Oct-18 58

59 Clinical Trials 26-Oct-18 59

60 Clinical studies are grouped according to their objective into three types or phases: Phase I Clinical Development (Human Pharmacology) - Thirty days after a biopharmaceutical company has filed its IND, it may begin a small-scale Phase I clinical trial unless the FDA places a hold on the study. Phase I studies are used to evaluate pharmacokinetic parameters and tolerance, generally in healthy volunteers. These studies include initial single-dose studies, dose escalation and short-term repeated-dose studies. 26-Oct-18 60

61 Phase II Clinical Development (Therapeutic Exploratory) - Phase II clinical studies are small-scale trials to evaluate a drug s preliminary efficacy and side-effect profile in 100 to 250 patients. Additional safety and clinical pharmacology studies are also included in this category. 26-Oct-18 61

62 Phase III Clinical Development (Therapeutic Confirmatory) Phase III studies are large-scale clinical trials for safety and efficacy in large patient populations. 26-Oct-18 62

63 Phase III Clinical Development (Therapeutic Confirmatory) While phase III studies are in progress, preparations are made for submitting the Biologics License Application (BLA) or the New Drug Application (NDA). BLAs are currently reviewed by the FDA s Center for Biologics Evaluation and Research (CBER). NDAs are reviewed by the Center for Drug Evaluation and Research (CDER). 26-Oct-18 63

64 Review of the lecture 26-Oct-18 64

65 Thank You Any questions? 26-Oct-18 65