Drug development

49 flashcards · Biology · by Ajay Pradhan

1. Peptide bond is between amino and carboxyl groups

2. What are the functions of peptides?

   Actions as hormones neurotransmitters growth factors ion channel ligands anti-infectives

3. What are the classifications of native peptides?

   Ribosomal peptides Non-ribosomal peptides

4. What are the geneticist's dilemma?

   Most mutations are recessive, loss-of-function Most mutations confer sensitivity, not resistance to a specific condition Screening of resistance is easy, simply selecting will do Screening for sensitivity is extremely labor-intensive, involves replica-plating and visual inspection

5. There are how many identified GPCR pathways in budding yeasts? What are they for?

   2 For glucose sensing and mating

6. The full form of SGA in regards to yeast studies is synthetic gene arrays

7. How many genes does C. elegans have? How many of them are essential?

   19000 genes Around 5000 of them are essential

8. How long is a C. elegans (adult)?

   1 mm

9. How long does it take a C. elegans to complete its life cycle?

   50 hours

10. What are C. elegans grown on in the lab?

    They are grown on E. coli lawns

11. How many cells does a C. elegans have?

    959 cells 302 neurons

12. What is the stage in the lifecycle of C. elegans called where it skips from L2 to L4 during harsh conditions?

    Dauer

13. What diseases are C. elegans used to study?

    CNS diseases Depression Psychosis Parkinson's Alzheimer's Pain Metabolic dieases Type II diabetes Obesity Other diseases Cardiovascular Oncology Muscle disease

14. About 70% of human genes have a clear C. elegans homolog.

15. What are the advantages of using C. elegans as a model organism?

    They are transparent so it enables visualization They are multicellular (959 cells) They have several conserved signaling pathways They are easy to grow and look after Short lifecycle Great for High throughput screening (HTS) Can be used to study aging processes because it passes through several distinct phasesof life which can be observed physiologically and genetically Good for studying neural development, because it has only 302 neurons and 7000 synpases making it simpler to study

16. What is the sequence of events that usually take place in a drug development pipeline?

    Target identification and validation Assay development Hits Leads Animals Clinic

17. Pharyngeal pumping in C. elegans is linked to voltage-gated channels for research.

18. Humanization is the expression of human genes to express human proteins in mutant organism that can perform the same function (homolog), thus saving their lives.

    Mutant worms rescued with human genes

19. How would you conduct an in vivo screen for ion channel modulators?

    Express human target in selected C. elegans physiology Identify a quantitative phenotypics effect dependent on activity of human gene Develop and assay for robust high throughput screen Screen chemical library Identify target hits

20. What are the C. elegans sorting/scoring machines dependent on?

    They dependent on fluorescence via: The worm taking up the dye (mutation/drugs alter this) The expression of GFP in the worm (The drug affects the expression of genes)

21. Nose hypercontraction is the sign of Prozac usage in C. elegans

    Also includes paralysis and sudden egg laying

22. How would you use C. elegans to identify genes through which a drug acts?

    Identify a compound-induced phenotype Do random mutagenesis Identify and molecularly clone mutant resistant to compound Identify human homologue ----------------------------------------------- Mutagenesis is done with EMS The identification of the genes in the clones involve the followeing Whole genome sequencing Outcrossing RNAi Rescue with wild type transgene

23. What do protein kinases control?

    Metabolism Transcription Cell cycle progression Cytoskeletal rearrangement Cell movement Apoptosis Differentiation

24. Protac can bind to proteins and cause its degradation via the proteolysis pathway.

25. What are the ways drugs target and cure diseases that occur with abnormalities in tyrosine kinases?

    Inhibit the protein-ligand interaction Promote degradation of the protein using something such as protac

26. How many kinase inhibitor drugs are there? What are they?

    There are 4 types They are: Type I (Competitive) Type II (Competitive + allosteric site) Type III (Allosteric inhibition - close to the ATP-bound pocket) Type IV (Allosteric inhibition - distant from the ATP-binding site)

27. What are some kinase inhibitor drugs?

    Glivec Rapamycin MEK1/2 inhibitors CDK inhibitors Covalent inhibitors

28. Glivec is a ATP-competitive inhibitor and is used for treating cancer

29. What are the possible improvements one looks for while optimizing leads (drugs)

    Increased solubility Increases bioavailability

30. What is bioavailability?

    Bioavailability is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of a drug. It refers to the degree and rate at which an administered drug is absorbed by the body's circulatory system

31. Glivec is a type -II inhibitor

32. What are the various classes of protein drugs?

    antithrombins clotting factors fibrinolytics antineoplastic agents hormones fertility agents enzymes antibodies immunosuppressive agents antidiabetic agents

33. What are the 3 important parts of collision theory?

    Reacting substances must collide They must collide with enough energy They must collide with the correct orientation

34. What is the collision model?

    The collision model is the model that describes chemical kinetics, which states that for a chemical reaction to occur, the molecules, atoms or ions need to collide with more than a certain amount of kinetics energy and in the proper orientation.

35. What are some of the common techniques used to study protein interaction with ligands?

    Surface plasmon resonance Isothermal titration caloriemetry Nuclear magnetic resonance

36. The full form of SWOT is strengths weaknesses opportunities threats analysis

37. The full form of DMTA is design make test analyze

38. The full form of FBLG is fragment based lead generation

    Candidate drug refinement and selection

39. What methods can be used for fragment screening?

    NMR X-ray

40. What is the central idea of fragment based lead generation?

    To start the hit and lead optimization process with small molecular fragments with molecular weight in the 120-300 Dalton range. Screening such small compounds is more likely to identify central scaffolds that can fit into the target binding site

41. What are the 3 essential elements of FBLG?

    a library of suitable fragments a method for identifying which fragments bind a strategy for evolving the fragments to larger hits for optimization to lead compounds

42. What are the things that chemical biology deals with?

    Target identification Target validation Lead generation (Phenotype screening) Lead optimization (Biomarker selection, probing selectivity) Clinical profile (combination therapies, understanding resistance)

43. What are the things that structural biology deals with?

    Lead generation (Library design, virtual screening) Lead optimization (Designing for potency, understanding selectivity) Clinical profile (Understanding resistance)

44. The DMTA cycle time is around 3 weeks and over 100 structures are determined. It takes place between hit and lead stage

45. What is a DMTA cycle?

    A DMTA (design make test analyse) cycle is the iterative process of designing new compounds, synthesizing them, testing them in various assays, and analyzing the results prior to next round of designs.

46. For SBDD to be an attractive technique, crystallographic system must be in place within 1-2 months, need iterative system

47. How does FBLG overcome the limitations of conventaional HTS?

    by increasing the novelty of leads - less dependence on existing compounds - early chemistry can be combined with protein structure to get high design component fragment leads have better biophysical properties small molecules and good solubility Increases the likelihood of finding a lead since fragments sample chemical space very effectively (also need less compounds)

48. What aspects impact the choice of microtiter plates?

    Method of detection (absorbance, fluorescence) Compatibility with biological reagents Cost of reagents impacts assay volume Available material impacts assay volume Liquid handling capability

49. What are the different sizes of microtiter plates 96 well 384 well 1536 well