Different Approaches of Drug Discovery

  • Created by: LBCW0502
  • Created on: 03-10-19 11:17
What is a lead compound?
First compound or structural motif of a new family of therapeutic agents to be discovered (rare for actual drug structure to be marketed). Potentially highly valuable financial assets (protect IP)
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Give an example of a lead compound which led to the generation of drugs in different therapeutic classes
Prontasil (antibacterial) led to the generation of - sulfanilamide, furosemide, carbutamide, acetazolomide
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Where do lead agents come from? (7) - 1
Screening (phenotypic, synthetic, natural products, existing drugs for re-positioning). Natural products. S/E (clinical observation/re-positioning). Metabolism studies. Serendipity (chance observation)
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Where do lead agents come from? (7) - 2
Rational drug design (structural biology/screening/molecular modelling/synthesis, small molecules). Biologics
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Describe features of screening for 'hits' (that may provide 'leads') - 1
Choose therapeutic area and target (e.g. protein, glycoprotein, nucleic acid). Choose and develop assay (manual, semi-high-throughput, high-throughput). Choose molecules/libraries/extracts to screen. Carry out screen/analyse data for 'hits'
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Describe features of screening for 'hits' (that may provide 'leads') - 2
Develop 'hit' to 'lead' - (medicinal chemistry/synthesis)
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What are the types of primary screens?
Enzyme based, receptor based, biochemical type (protein, DNA, RNA, sugars), cell based (in vitro), in vivo (e.g. zebra fish embryos) - can be manual, semi-throughput, HTS, fluorescence (radioactive labelling)
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Give an example of an enzyme-based assay
Donor bound to quencher via peptide bond. Protease enzyme breaks peptide bond. Quenching (no fluorescence seen). Quenching lost (fluorescence seen). Inhibition of protease, quenching remains, no fluoresence
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Describe features of imatinib mesylate (Gleevec)
(Low through-put screening used in discovery of imatinib, bound to ATP binding pocket of BCR-ABL protein). Tyrosine kinase inhibitor (highly specific for BCR-ABL/associated with CML and ALL). Also shown to inhibit KIT and PDGF receptors
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Give examples of sources of natural products (4)
Plants/trees, bacteria/fungi (streptomyces), marine organisms, animals
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Describe features of plants and trees
Produces large numbers of organic molecules/rich in stereochemical centres. Unknown reason for production (could be for attack/defence). Warfarin discovered from plants. Isolation of API is difficult, used for commercial production of drugs
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Give examples of drugs which were discovered in plants/trees
Sennosides A and B (laxative, from the Alexandria senna plant) and galantamine (AChE inhibitor from daffodils)
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What is the plant source for digoxing?
Foxglove (Digitalis purpura)
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Describe features of ingenol mebutate (Picato gel)
API derived from sap of plant Euphorbia peplus (petty surge/milkweed) - used for actinic keratosis (starting signs of skin cancer, rash/sunburn on the face)
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What is the main source of anti-cancer drugs?
Natural products (65%)
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Describe features of vinblastine and vincristine
Screening programme for agents with potential hypoglycaemic properties led to isolation of the alkaloids as minor constituents of Madagascar periwinkle (Vinca rosea)
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Describe features of Paclitaxel
Tetracyclic dilterpene derived from bark and needles of the Pacific yew tree (Taxus brevifolia). Docetaxel (Taxotere) introduced as semi-synthetic analogue with similar therapeutic/toxicological properties
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Which terms are used to study the presence of drugs in plants/trees?
Pharmacognosy. Natural products research. Ethnobotany. Ethnopharmacology
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Give examples of important drugs produced by bacteria and fungi
Penicillin (penicilium notatum). Chloramphenicol (streptomyces venezuelace). Griseofluvin (penicillin grisofullivum). Streptomycin (streptomuces griseus). Neomycin (streptomyces fradiae)
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Give an example of a drug derived from marine organisms
Trabectidin (Yondelis), derived from sea squirt. ET-743 - DNA binding agent, activity against melanoma, breast, ovarian, colon, renal and non-small cell lung and prostate carcinomas cell lines. Evaluated in clinic against soft tissue sarcomas
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Give examples of drugs derived from animals
Premarin (conjugated oestrogens, Wyeth), derived from urine of pregnant mares. Manuka honey (and cough mixtures)
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Give examples of lead molecules discovered through side effects (clinical observations) (1)
S/E or ADR leads to a new therapeutic indication for the drug e.g. phenytoin (from phenobarbital which was a sedative/hypnotic, reduced seizures in epileptic patients)
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Give examples of lead molecules discovered through side effects (clinical observations) (2)
Viagra (sildenafil developed as anti-hypertensive treatment, observed S/E of helping with ED). Minoxidil (prevent hair loss). Ropinirole (originally used to treat PD, positive S/E on restless leg syndrome and SSRI-induced sexual dysfunction)
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What is drug re-positioning?
Purposeful research to see whether an existing drug may have an application in a different therapeutic area and/or for a new indication
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Give examples of re-positioned drugs
Pregabalin (Lyrica) and ropinirole (Requip). Viagra. Thalidomide. Buprenorphine. Colesevelam. Plerixafor. (Discovered through side effects)
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What are compound libraries?
Used for re-positioning studies, to search to number of molecules targeting specific disease areas
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Give an example of experimental re-positioning
Phenytoin as potential anti-cancer agent (inhibits breast tumour growth and metastasis)
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Give examples of metabolism studies
Desipramine (anti-bulimic) from imipramine (for major depression). Temazepam from diazepam. Exiculind from Sulindac. Paliperidone from risperidone. Fluoxetine from paroxetine
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Describe features of temazepam
Metabolite of diazepam, more polar, faster onset/shorter duration of action, used for insomnia, anxiolytic agent. Discovered using liver cell culture techniques and HPLC techniques
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Give examples of drugs discovered from chance observations (serendipity)
Diazepam, nitrogen mustards, cisplatin, penicillin, LSD, vorinostat
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Describe features of cisplatin (1)
Discovered when observing an alternating electric current through platinum electrodes in an electric cell containing E.coli led to arrest of cell division without killing cells
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Describe features of cisplatin (2)
Continued growth without division led to elongated cells/spindle like appearance. Cytostatic effect traced to platinum complexes formed in presence of ammonium salts and light. Cisplatin binds to DNA. Newer generations - carboplatin, oxaliplatin
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What is the first example of rational drug design?
Pralidoxime (MOA - reverses poisoning from nerve gas, regenerated AChE)
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What is molecular pruning? (1)
Chop away portions of a biologically active molecule to try to evaluate the pharmacophore. interactive part of drug may interfere with fit at receptor through steric interaction. Non-pharmacophore may be important for ADME. Chop molecule down.
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What is molecular pruning? (2)
Find essential parts. Very precise interaction of drug/receptor (agonist/antagonist)
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Give an example of a drug which has undergone molecular pruning
Morphine - form analogs (morphinan, levorphanol. Increased pruning - morphine, codeine, heroin, morphinan, levorphanol, benzomorphan, cyclazocine, pentazocine, merepidine, dextropropoxyphene, methadone, tramadol
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What is the pharmacophore for morphine?
Aromatic ring, quaternary carbon, tertiary nitrogen
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Give examples of conformationally restricted analogs
Morphine restricted to form buprenorphine (more potent) then etorphine (more potent)
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Describe features of bioisosteres and functional group manipulation
Substitution of atoms and rings with different ones of similar shape, volume and electron distribution/charge. Developed during work on anti-histamines. Can change inhibitor to agonist. Can change ADME characteristics. Create 'me too' drugs
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Give examples of atoms and functional groups
S to CH=CH, N to CH=, O to C=/NH/CH2, CH3 to H/F/OH/NH2
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Give examples of smaller and larger ring systems
Mono, bi and tri (rings with functional groups, N, S, O). Smaller and larger ring systems
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Give an example of ionising systems
COOH can be converted to other functional groups NH, OH, phenol
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Give an example of 'me too' drugs
Cimetidine and ranitidine
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What are conjugates?
Joining two entities together to obtain a synergistic therapeutic effect, formulation/delivery benefit or for targeting purposes (drug-drug, antibody-drug, two component systems)
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Give an example of a conjugate
Benorylate (join aspirin and paracetamol with ester bond). Analgesic, anti-inflammatory, anti-pyretic (no used as much due to fixed dose, easier to regulate dose for either aspirin or paracetamol)
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What are prodrugs?
Chemical modification of an active therapeutic agent to improve bioavailability or reduce toxicity upon administration. A prodrug is converted back to biologically active therapeutic agent via chemical or enzyme reactions (hydrolysis, peptidase)
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Give an example of an enzymic conversion
Reductive cleavage of sulfasalazine to form sulfapyridine and 5-aminosalicylic acid (prodrug to target IBD). Salazopyrin
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What are biochemical and physiological studies?
Study metabolic pathways, enzyme mechanisms and other physiological studies (e.g. transmitters). E.g. 5-FU and methotrexate, para-metabolites. Many drugs originated from studies e.g. histamine, serotonin, noradrenaline, dopamine
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Which drug was discovered through biochemical studies on noradrenaline?
Salbutamol (Ventolin) - bronchodilator (selective beta-2-agonists), short acting
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Which drugs were discovered through biochemical studies on histamine?
Ranitidine and cimetidine
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Which drugs were discovered through biochemical studies on serotonin?
The triptans
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Which drugs were discovered through biochemical studies on dopamine?
L-DOPA
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Describe features of structural biology-based approaches
First elucidate structure of protein then physical/virtual screen. Use of crystallinography to determine 3D model. Main techniques are NMR and X-ray
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What are the potential problems with molecular modelling?
Potential conformational changes of ligand/receptor upon binding. Molecular dynamics stimulations/more computer power needed. Correct energy minima. Solvation. Metal ions
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Give an example of a drug partly discovered through molecular modelling
Imatinib mesylate (Gleevec)
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What do computational methods consist of?
Molecular modelling and virtual screening e.g. STAT3 dimer bound to DNA
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Describe features of genomics (1)
DNA (genetic information of each cell). Human genome project should be exploited to discover new drugs. Associated gene with particular disease, try to turn off gene, up-regulate if protein missing or insert healthy gene
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Describe features of genomics (2)
E.g. up-regulated oncogene in cancer, faulty gene in CF and muscular dystrophy. Tools - antisense oligonucleotides, RNAi, small molecules, SNA arrays, proteomics, transcription factors, CRSPR, gene knockout, point mutation/insertion/correction
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Describe features of genomics (3)
Large gene knock in, reporter gene knock in, inducible gene expression, gene over expression, custom heterozygous or homozygous mutations
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What are the potential applications for genomics?
Cancer, anti-tumour agents, anti-fungals, anti-bacterials, anti-virals, anti-parasitic, other diseases. Tools for functional genomics and target validation. Therapeutic strategies based on nucleic acid sequence recognition (DNA/RNA, proteins)
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What is the antisense approach?
mRNA in nucleus binds to antisense DNA oligonucleotide, no translation, prevent formation of proteins. Major problems - stability, delivery, off-target effects
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Give examples of two anti-sense based drugs approved by the FDA in the USA
Fomivirsen and mipomersen
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What are biologics (biopharmaceuticals)?
Medicinal product extracted from biological sources e.g. vaccines, recombinant therapeutic proteins, glycoproteins, enzymes, antibody therapies, blood components, allergenics, cells, gene therapeuties, tissues interferon
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Give examples of biologics
CTLA-4 and PD-1 (immunology), CAR-T therapy (can be discovered through rational drug discovery approach)
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Summarise the best method to discover new lead molecules
Discover target, find structure associated with signalling pathway elucidated. Physical assay established. Agonists or antagonists identified. Consider in silico screening to produced further 'hits'
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Prontasil (antibacterial) led to the generation of - sulfanilamide, furosemide, carbutamide, acetazolomide

Card 3

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Card 4

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Card 5

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Describe features of screening for 'hits' (that may provide 'leads') - 1

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