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PA20321 Retake > (chan) 2. Medicines Design > Flashcards

(chan) 2. Medicines Design Flashcards

1
Q

What is PFK-1 and its characteristic?

A
  • Primary control enzyme of glycolysis
  • Allosteric enzyme composed of 4 subunits
  • ATP is both substrate and allosteric effector
  • High activity: Michaelis-Menten Kinetics
  • Low activity, Sigmoidal Kinetics
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2
Q

What are the inhibitors and activators of PFK-1 enzyme?

A

Inhibitor
- ATP, citrate, H+

Activator
- AMP

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3
Q

Describe TCA(Tricarboyxlic acid) cycle

A
  1. Oxaloacetate and Acetyl-CoA are condensed
  2. Citrate is rearranged to isocitrate by cis-aconitase
  3. Isocitrate is oxidised and decarboxylates
  4. 2-Oxoglutarate is decarboxylased by 2-OG dehydrogenase complex
  5. Succinyl-CoA is converted to succinate
  6. Desaturation and formation of FADH2
  7. Hydration
  8. Oxidation and formation of NADH
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4
Q

How is the TCA cyle regulated?

A
  • Primary control enzyme is pyruvate dehydrogenase complex
  • High energy signals and products of TCA cycle are inhibitors
  • ADP increases activity of isocitrate dehydrogenase
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5
Q

What is anaplerotic reaction regarding TCA cycle?

A
  • ‘Filling up’ Process
  • TCA cycle is used to provide starting materials for biosynthesis
  • This results in depletion of oxaloacetate
  • Acetyle-CoA accumulates
  • High levels of Acetyl-CoA ↓ pyruvate dehydrogenase complex and ↑ pyruvate carboxylase
  • Net effect is to rebalance oxaloacetate and acetyl-CoA levels
  • Production of oxaloacetate is also important for gluconeogenesis
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6
Q

What is the Cori cycle?

A
  • Recycling R-lactate to glucose
  • Lactate is transported from muscle to liver in blood
  • Lactate dehydrogenase in liver converts R-lactate to pyruvate
  • Pyruvate is converted to glucose by gluconeogenesis
  • Process requires input of 6 x ATP per glucose molecule
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7
Q

What are glycolysis and gluconeogenesis regulated by?

A
  • Both glycolysis and gluconeogenesis take place in the cytosol

Glycolysis and Gluconeogensis reciprocally controlled by 2 processes
- Energy levels in the cell
: Signalled by ATP, ADP, AMP, citrate

  • Hormonal control (glucagon)
    : Signalled by fructose-2,6-bis-phosphate levels
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8
Q

What is Glucagon and its role?

A
  • Hormone secreted in response to low blood glucose levels
  • Binding to a receptor initiates cAMP-mediated signalling
  • This activates protein kinase A (PKA)
  • PFK-2 is phosphorylated by PKA
  • F-6-P kinase activity is reduced
  • F-2,6-BP phosphorylase activity is increased
  • pyruvate kinase is phosphorylated, reducing activity
  • Activity of the glycolysis pathway is reduced
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9
Q

What is insulin and its role?

A
  • Hormone secreted in response to high blood glucose levels by the pancreas
  • Has opposite effect to glucagon
  • In fed state, it increases the GLUT4 concentration enabling uptake of glucose into muscle and adipose cells
  • It counteracts the inhibitory effect of glucagon by reducing phosphorylation PFK-2 / phosphatase and pyruvate kinase
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10
Q

What is the effect of adrenaline on glucose metabolism?

A
  • Adrenaline is a hormone produced in response to stress and exercise
  • Stress response requires glucose to be mobilised to produce ATP
  • Therefore glycogen breakdown is stimulated and glycogen synthesis is inhibited in a similar manner to glucagon
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11
Q

Describe Electron transport system regarding ATP synthesis

A
  • Under anaerobic conditions, the reduced electron acceptors in the transport system are not re-oxidised
  • Terminal acceptor for the system is dioxygen
  • This means that entry of pyruvate and flux through TCA cycle is reduced
  • Pyruvate is converted to lactate instead to maintain NAD+ level in the cytosol
  • Lactate is recycled via the cori cycle
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12
Q

How does glucagon induce increase in glucose?

A
  • Glucagon binds to its receptor, which produces cAMP
  • This activates protein kinase A which phosphorylates target enzymes
    : 1. Phosphorylase kinase is activated
  1. This activates glycogen phosphorylase
  2. Glycogen synthase is inhibited
  3. More glucose is produced
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13
Q

What is the key process regulating fatty acid β-oxidation and biosynthesis?

A
  • Synthesis of malonyl-CoA
  • High level of malonyl-CoA allow fatty acid biosynthesis
  • Malonyl-CoA inhibits import of fatty acids into mitochondria for degradation
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14
Q

What is the overall effect of ‘Glucagon’? (Summary)

A

Increases blood glucose level by cAMP-mediated acitvation of PKA which causes

  • Phosphorylation of glycogen synthase and glycogen phosphorylase, releasing glucose from glycogen
  • Phosphorylation of PFK-2 and pyruvate kinase reducing glycolysis
  • Increase in fructose-1,6-biphosphatase and glucose-6-phosphatase in the cell inccreases gluconeogenesis
  • Activatio nof triacyl-glycerol lipase, releasing fatty acids for β-oxidation
  • Phosphorylation of acetyl-CoA carboxylase which lowers malonyl-CoA level reducing fatty acid biosynthesis
  • Increased acetyl-CoA levels activate pyruvate carboxylase in TCA cycle anaplerotic reaction, increasing oxaloacetate for gluconeogenesis
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15
Q

What is the overall effect of ‘Insulin’? (Summary)

A

Secreted from the pancreas in response to high blood glucose levels which causes

  • Increased GLUT transporters in muscle and adipose tissue allowing glucose uptake
  • reduced phosphorylation of glycogen synthase and glycogen phosphorylase promoting glycogen synthesis
  • reduced phosphorylation of PFK-2 and pyruvaate kinase increasing glycolysis
  • Increased level of glycolytic enzymes and reduced gluconeogenic enzymes
  • Decreased phosphorylation of acetyl-CoA carboxylase, increasing malonyl-CoA. This increases fatty acid biosynthesis
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16
Q

What is the effect of glucocorticoids on glucose and lipid metabolism?

A
  • High levels of glucocorticoids promote biosynthesis of gluconeogenic enzymes and suppresses production of glycolytic enzymes
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17
Q

How is ketone bodies formed in diabetic patients?

A
  • In diabetes or starvation glucose is scare
  • Brain and erythrocytes are particularly dependent on glucose for energy
  • Fatty acids are degraded to acetyl-CoA to make up the short-fall
  • Three molecules of acetyle-CoA are used to acetoacetate and 3-hydroxybutyrate by the mevalonic acid pathway
  • These are distributed by the blood and can be used as fuels instead of glucose
  • Acetoacetate is easily converted to acetone hence the solvent smell on the breath
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18
Q

(JUST READ)

Summary of Overview of carbohydrate and lipid metabolism and hormonal control

A
  • The metabolism of glucose, fatty acids is coordinated to maintain the required levels of ATP
  • Control enzymes usually exist at the concomitant point (where pathway becomes unique)
  • Increasing and decreasing activity changes flux of metabolites through various pathways
  • Activity of control enzymes is controlled by cellular signals and hormones
  • Glucagon produces its effect by cAMP-mediated activation of Protein kinase. Phosphorylation of control enzymes changes their activity
  • Insulin blocks glucagon signaling and reverses its effects (causes dephosphorylation)
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19
Q

What is a Glycation reactions?

A
  • non-enzymatic reaction of sugars(glucose) with nucleophilic groups
  • Reaction is at various sites
  • Derivatives can further react to produce advanced glycation products (AGP)
  • Glycation of haemoglobin often used to measure glucose control in diabetic patients
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20
Q

What is Hexose monosaccharides?

A
  • Monosaccharide with 6 carbons
  • Glucose is the most abundant hexose
  • Galactose and Mannose are epimers of glucose
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21
Q

How is anomers formed?

A
  • Addition of alcohol group to aldehyde forms a hemiacetal
  • Presence of OH group on carbon-5 means a 6 membered ring is formed
  • A new chiral centre is formed on hemiacetal formation, which can have one of two configurations (α- or β-)
  • These new isomers are called anomers
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22
Q

Glycation can only occur with reducing sugars. True or False?

A

True

  • Reducing sugars reduce Cu2+ and Ag+ ions in basic solution and are themselves oxidised
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23
Q

What is the Amadori reaction?

A
  • Rearrangement mediated by protonation/deprotonation
  • Reversible
  • Further oxidative and non-oxidative reactions can occur to give Advanced Glycation Products (AGPs)
24
Q

What is the consequences of Glycation?

A
  • Recognised as a major cause of Diabetic secondary complications including nephropathy, retinopathy and atherosclertosis
  • Glycated proteins are difficult to degrade so there is a build-up of damaged proteins in the cell
  • Damage results in production of auto-antibodies, resulting increased level of inflammation
25
Q

What techniques can be used to measure glycation products?

A
  • Ion-exchane chromatography
  • Affinity chromatography or gel electrophoresis
  • Isoelectric focussing (detecting changes in isoelectric point of the protein)
  • Immunoassays such as ELISA which detect particular antigen
  • Inflammation causes production of several inflammatory markers
26
Q

(JUST READ)

Summary of Glycation & Monitoring

A
  • Reducing sugars such as glucose contain highly reactive aldehyde groups
  • These aldehydes can react with amines to form imines condensatio n products
  • Rearrangement of the imine gives the Amadori product
  • Further reaction of the Amadori product by oxidative and non-oxidative pathways give rise to Advanced Glycation Products (AGPs)
  • The most important protein residues in terms of glycation are internal lysines
  • Reaction with other protein residues and other biomolecules occur
  • Glycation is thought to be responsible for the majority of diabetic complications and there are a number of analytical methods to measure this
  • There is no proven therapy to reduce glycation, but amines such as pyridoxamine, reducing agents and plant extracts and drugs such as penicillamine may be of use
27
Q

Describe Classical Potential Energy Methods

A
  • Energy of a molecule calculated using a potential energy function which generally only considered how close non-bonded atoms are to each other
28
Q

What is the aim of Conformational Searching via Classical potential energy methods?

A
  • To locate low energy conformations as it is unlikely that high energy conformers are common enough to be involved in biological processes due to having Boltzman distribution of energies
  • Low energy conformations are frequently used as starting points for more sophiscated calculations
29
Q

What does Potential Energy Map show?

A
  • illustrates the charge distributions of molecules three dimensionally
  • These maps allow us to visualize variably charged regions of a molecule
30
Q

Describe Molecular Mechanics Optimisation

A
  • Optimising the structure of a single conformation of a molecule by altering the geometry of the molecule slight so that a more realistic structure is generated
31
Q

What is a Force Field?

A
  • Overall potential energy of the molecule calculated through a combination of energy functions
32
Q

What is Molecular Mechanics Minimisation?

A
  • Mathematical process whereby the structure obtained by a round of calculation processes is compared to a previous structure
  • The structure is modified to make it more consistent with the parameter information within the program

common methods)

  • steepest descent
  • Newton-Raphson method
  • simplex method
  • Fletcher-Powell method
  • combination of methods
33
Q

Describe Optimisation Process

A
  • Components contributing to the energy are calculated

- Those making the greatest contribution to the energy are changed in order to make the energy fall

34
Q

Force fields used for Optimisation are essentially divided into two classes. What are they?

A

1 ‘all atom’
- The first is for use with small molecules with all atoms including hydrogen atoms

  1. essential atoms only
    - for biological molecules
    - majority of hydrogen atoms are removed to decrease computational time
35
Q

Best-known molecular mechanics for 1. small molecules and 2. large molecules?

A
  1. small molecule
    - MM2
  2. large molecule
    - AMBER
36
Q

What is the problem of Local minima?

A
  • Major problem with molecular mechanics calculations is that they converge on the nearest local minimum which is not necessarily the global minimum
37
Q

Describe Molecular Dynamics

A
  • Method using the Newtonian equations of motion, a potential energy function and associated force field to follow the displacement of atoms in a molecule over a certain period of time, temperature and pressure.
38
Q

What is Simulated Annealing?

A
  • Special type of dynamics where the molecule is heated and then cooled very slowly so that conformational changes taking place will lead to a local minimum being located
39
Q

What is Monte Carlo Methods?

A
  • Moving molecules randomly to a new geometry/conformation
40
Q

What is Crystal regarding molecular modelling?

A
  • periodic arrangement of uni cells in a lattice

- The unit cell is repeated in a 3-D lattice to make a crystal

41
Q

What is X-ray crystallography?

A
  • method determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and scatters into many different directions
  • From the angles and intensities of these scattered beams, a crystallographer can produce a 3D picture of the density of electrons within the crystal
42
Q

What is Homology Modelling?

A
  • Suppose you want to know 3D structure of a target protein and have the unknown sequence and a sufficiently similar protein (50% or better identity)
  • You can use software that aaranges the backbone of your sequence identically to the template
43
Q

What are the 3 items of input needed for Homology Modelling?

A
  • Target sequence
  • 3D template sequence
  • Alignment between target sequence and template sequence
44
Q

What are the examples of lead compound o drug discovery?

A
  • Natural receptor ligands, enzyme substrates
  • Collections of synthetic compounds
  • Existing drugs
  • Natural products
  • Computer-aided rational design
45
Q

What does “SWOT” stand for in the analysis finding peptide and protein therapeutics?

A

S: Strength
- good efficacy

W: Weakness
- Chemical and physical stability

Opportunities
- Discovery of new peptides

Threats
- Immunogenicity

46
Q

What does British Pharmacopoeia Monograph provide?

A
  • description of a pharmaceutical
  • specification of required level of purity
  • descriptions of tests to identify the substance and monitor possible impurities
  • Specify an assay to determine the amount of substance
47
Q

Which peptide and protein analysis method is particularly suitable for peptides?

A
  • Reversed Phase HPLC (RP-HPLC)
48
Q

What does insulin consist of?

A

2 Chain peptide consisting of 51 amino acids

  • Chain A = 21 amino acids
  • Chain B = 30 amino acids
  • 2 x interchain disulfide bonds (A7→ B7; A20→ B19)
  • 1 x interchain disulfide (A6 → A11)
49
Q

What is Peptide Mapping?

A
  • Identity test for peptides and proteins
  • chemical or enzymatic cleavage of the peptide backbone in specific locations generates a set of fragments, which upon separation and identification provide a ‘fingerprint’
50
Q

What is incretins?

A
  • gastrointestinal hormones that increase insulin release from the pancreas in response to elevated serum glucose levels
51
Q

(JUST READ)

Summary of ‘Development of Peptide and Peptide Analogues’

A 
Development of non-peptide and peptide antidiabetic agents and the importance of physicochemical 
- lead compounds of both class derived from a range of sources; Lipinski properties related to typical mode of administration

Identification and characterisation of therapeutic peptides
- peptide mapping as a tool to distonguish closely related synthetic analogues

Incretin mimetics as antidiabetic agents
- stabilising natural peptides vs inactivation by DPP-4

52
Q

Patients with T2DM produce normals levels of GIP (glucose-dependent insulinotropic polypeptide) but show lower sensitivity, while GLP-1(Glucagon Like Peptide-1) maintains its full efficacy, but is produced to a lesser extent

What are the 2 therapeutic strategies?

A
  1. Develop incretin mimetics (analogues of GLP-1) with extended plasma t1/2
  2. Prevent the inactivation of both incretins (GIP and GLP-1)
53
Q

Most proteases may be divided into 4 distinct groups according to the chemical nature of their active sites.

What are they?

A
  1. Serine Protease
    eg) DDP-4 aka dipeptidyl-peptidase-4
  2. Cysteine protease
    eg) papain, cathepsin)
  3. Aspartic protease
    eg) pepsin, renin, HIV-1 protease
  4. Metalloprotease
    eg) ACE, MMPs
54
Q

What is the role of SGLT2 (Sodium-Glucose cotransporter 2) regarding glucose level?

A
  • controls glucose homeostasis in the kidney

- Inhibition of SGLT2 therefore recognised as a potential therapeutic target for treatment of T2DM

55
Q

(JUST READ)
Summary of ‘Development and SAR of DPP4 inhibitors (gliptins) and SGLT2 inhibitors
‘

A 
Principles involved in developing an inhibitor of a specific class of protease
- design of inhibitors of serine protease

Design of DPP-4 inhibitors as antidiabetic agents
- design of covalent and non-covalent inhibitors

Development of current SGLT2 inhibitors and their pharmacophore
- natural product-inspired antidiabetic agents

PA20321 Retake (5 decks)

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