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MBB261 > Baker - pushing electrons & drug development > Flashcards

Baker - pushing electrons & drug development Flashcards

1
Q

What does a reaction mechanism of a catalytic cycle show?

A
  • determines where electrons are
  • decides which bonds broken and which made
  • describes flow of e-s
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2
Q

In what level of hybridisation are most molecules?

A
  • sp3
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3
Q

What is the arrangement of an sp2 hybridised molecule?

A
  • planar trigonal
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4
Q

How is a σ bond formed in methane?

A
  • 1s orbital of H overlaps w/ sp3 orbital of C
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5
Q

What bonding is there in ethene?

A
  • σ bond formed between C-C (sp2-sp2 overlap)
  • σ bond formed between C-H (sp2-s overlap)
  • π bond formed between C-C (p-p overlap)
  • double bond between C-C (4 e-s shared)
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6
Q

What is a π bond?

A
  • regions of e- density above and below internuclei axis, but none along axis
  • so no free rotation between 2 C atoms
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7
Q

What do Lewis structures show?

A
  • represent e-s in a structure
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8
Q

What is the process of working out a Lewis structure?

A
  • write mol skeleton
  • assume all bonds covalent
  • count available valence e-s
  • add σ bonds and give each atom 8e-s (2 for H)
  • if no. e-s in structure same as valence e-s then correct
  • if larger add π bonds
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9
Q

Is sp hybridisation common?

A
  • no, triple bonds rare
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10
Q

What arrangement does sp hybridisation give?

A
  • linear
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11
Q

What is formal charge?

A
  • charge assigned to atom in molecule, assuming e-s in bonds shared equally
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12
Q

How is formal charge calc?

A
  • count total no. e-s contributed from each element
  • what group is that element?
  • group no. - total no. e-s
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13
Q

Why do some molecules have more than 1 poss Lewis structure?

A
  • indiv representations of ONE actual structure
  • due to e-s being delocalised across no. of atoms
  • some structures more likely than others
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14
Q

What is the actual structure when there are multiple poss Lewis structures?

A
  • weighted av of diff resonance structures
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15
Q

What do diff Lewis structures of same molecule have in common?

A
  • same relative positions of all atoms in compound
  • same no. paired and unpaired e-s (sum of formal charge identical)
  • all important ones have similar energies
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16
Q

What do curly arrows show?

A
  • direction of e- movement
  • base at original location of pair of e-s
  • head at destination of e-s
  • 2 barbs = pair of e-s
  • 1 barb = single e-
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17
Q

What are the Bronsted definitions of an acid and base?

A
  • acid = proton donor

- base = proton acceptor

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18
Q

What are the Lewis definitions of an acid and base?

A
  • acid = can coord w/ lone pair of e-s

- base = lone pair of e-s available for sharing

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19
Q

If [A] / [HA] = 1 then what is the ratio of [H] to [HA]?

A
  • they are equal
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20
Q

How can the Henderson-Hasselbach equation be rearranged when pH = pKa?

A
  • log10 ( [A] / [HA] ) = 0

- 10^0 = 1, therefore [A] / [HA] = 1

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21
Q

What are the factors that determine acidity of the organic compound Y-H?

A
  • strength of Y-H bond
  • electronegativity of Y
  • factors that stabilise Y- compared to YH
  • nature of solvent
  • for enzymes need to consider –> electronegativity of Y and stability of conjugate base
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22
Q

Which are the stronger acids out of Asp, Ser, Tyr?

A
  • Asp (pKa ≈ 4.5) –> electronegative, 2 resonance structures, -ve charge delocalised in π system, conjugate more stable, therefore a weak acid
  • Tyr (pKa ≈ 10) –> O electronegative and -v charge moves around ring
  • Ser (pKa ≈ 15) –> O fairly electronegative but no other stabilisation, therefore NOT an acid
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23
Q

What causes the diff in pKa between Asp, Ser and Tyr?

A
  • stability of conjugate base
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24
Q

What 2 routes can drug dev follow?

A
  • compound –> physiological effect –> mol target

- mol target –> compound –> physiological effect

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25
Q

How can drug candidates bind to target molecules?

A
  • DIAG*
  • H bonding
  • hydrophobic cleft (Ile, Ala, Val)
  • stacking of planar aromatic ring w/ others, forming π interactions
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26
Q

Where was aspirin derived from?

A
  • salicylic acid
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27
Q

Why were derivatives of salicylic acid made?

A
  • known to have lots of effects, eg. reducing inflammation

- but acidic, so problems w/ irritation and absorption in stomach

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28
Q

What is the structure of aspirin?

A
  • DIAG*

- acetylsalicylic acid

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29
Q

How does aspirin act on cyclooxygenase component of prostaglandin H2 synthase, and what are the results?

A
  • acylates crucial Ser in cyclooxygenase
  • DIAG*
  • acylated Ser blocks hydrophobic tunnel, preventing substrate arachidonic acid from reaching active site
  • prostaglandin synthesis blocked
  • signalling pathways interfered w/ –> affects inflammation, fever, pain, blood clotting
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30
Q

Why do drug candidates often contain chiral centres?

A
  • chirality v important in binding to target
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31
Q

What is the structure of ibuprofen, and what form is this?

A
  • DIAG*

- S (active) form

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32
Q

How is ibuprofen related to aspirin?

A
  • inhibits same enzymes and has similar effects
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33
Q

In what form is ibuprofen sold?

A
  • racemic mixture

- and body converts all to S form

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34
Q

How was chirality a problem in relation to thalidomide, and how is thalidomide now used?

A
  • 1 form had therapeutic effects and other causes problems w/ dev of foetus
  • tried to make chirally pure, but body converts it back to both forms
  • used now in leukemia patients where no risk of affecting a foetus
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35
Q

What do the majority of drugs target, and why is this a problem?

A
  • at least half target membrane proteins

- problem as determining structure difficult, so hard to design drugs

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36
Q

What are some of the common drug targets?

A
  • enzymes
  • G protein-coupled receptor
  • VG ion channels
  • solute carriers
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37
Q

What is Kd a measure of, and what does a low value mean?

A
  • strength of interaction between drug candidate and target

- lower Kd = stronger interaction

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38
Q

How is Kd calc in relation to ligand binding in drug dev?

A
  • DIAG*
  • RL R + L
  • Kd = [R] [L] / [RL]
39
Q

How is the fraction of binding sites calc?

A
  • [RL] / [R] + [RL]
40
Q

What is true about the Kd equation for ligand binding if half binding sites are occupied?

A
  • [RL] = [R]
41
Q

What is a biological assay which can be used for drug potency?

A
  • DIAG*
  • biological response (%) (=bacteria killed) against [ligand]
  • EC50 = conc to elicit 50% response
  • EC90 = conc to elicit 90% response
42
Q

When is IC50 analogous to EC50?

A
  • when target is enzyme
43
Q

How can enzyme activity (%) be compared to [I]?

A
  • DIAG*
  • IC50 = conc of inhibitor to elicit 50% reduction in activity
  • IC90 = conc of inhibitor to elicit 90% reduction in activity
44
Q

How does the conc of substrate affect conc of drug req to inhibit enzyme?

A
  • DIAG*
  • if Km small (high affinity) then [S] high and IC50 = Ki x big no.
  • if Km large (poor affinity) then [S] low and IC50 = Ki x small no.
45
Q

What is Ki?

A
  • inhibition constant analogous to Kd –> a specific type of Kd
46
Q

How is IC50 calc?

A
  • IC50 = Ki (1 + [S] / Km)
47
Q

Why do we need to consider selectivity of drug molecule?

A
  • foreign molecule, so need to consider if binds to other proteins, DNA, RNA, metabolites, lipids etc. in cell
48
Q

How is selectivity of a drug molecule calc, and what value is wanted?

A
  • Kd binding of drug to other molecules / Kd binding of drug to target molecules
  • want small value
49
Q

What are effects caused by drug binding to other molecules known as?

A
  • off target effects –> can be good or bad
50
Q

Why do pharma companies want most drugs to be taken orally?

A
  • IV much more expensive
51
Q

What is the problem w/ taking drugs orally?

A
  • need to be absorbed from stomach into bloodstream
52
Q

What is the conc of drug at target site affected by?

A

ADME

  • Absorption (getting into blood)
  • Distribution (travelling around body)
  • Metabolism (drugs xenobiotic so need to stop metabolism getting rid of them, OR metabolism may turn them into more active form = prodrug
  • Excretion
53
Q

How do drugs reach their targets, and why must they have suitable properties to do this?

A

DIAG

54
Q

What is Lipinski’s rule of 5?

A
  • poor absorption likely when…
    1) mol weight > 500
    2) no. H bond donors > 5
    3) no. H bond acceptors > 10
    4) partition coefficient, log(P) > 5
55
Q

What is the partition coefficient?

A
  • tendency for molecule to dissolve in membranes –> want hydrophobicity so can dissolve, allowing diffusion, as active transport would req energy
  • correlates w/ ability to dissolve in organic solvents compared to aq solvent
56
Q

How is the partition coefficient found?

A
  • compare by measuring solubility in water and octanol
  • [ligand] (aq) [ligand] (1-octanol)
  • log(P) = log10 [ligand (1-octanol)] / [ligand (OH)]
57
Q

What would a log(P) value of 5 mean?

A
  • 100,000x more soluble in hydrophobic than aq solvent

- would be so hydrophobic that would race through membrane into aq blood and come out of solution

58
Q

Why are some drugs fluorinated, and when is this done?

A
  • often makes it more bioavailable

- done if they have good effects but poor ADME properties

59
Q

How is fluorination poss?

A
  • fluorine is good mimic of hydrogen
  • VdW radius F = 1.45Å and H = 1.1Å
  • C-F bond length = 1.35Å and C-H = 1.1Å
  • is slightly bigger than H, but smaller than C=O, so has v little steric effect
60
Q

What can sub of C-H for C-F in pharmaceuticals achieve?

A
  • alt lipophilicity (usually increase in log(P))
  • increase binding affinity of ligand to target (Kd)
  • improve metabolic stability (M of ADME)
  • increase bioavailability (A of ADME)
61
Q

What effect does the electronegativity of fluorine have on drug compounds?

A
  • v electronegative so can shift pKa of neighbouring group

- adding F decreases basicity of neighbouring group, so compound more lipophilic, so distributed better

62
Q

In what cases does fluorination not improve lipophilicity, and why might this be?

A
  • when F adj to O (approx when F<3.2Å from O)
  • due to polarisation of O leading to stronger H-bonds to water
  • or increase in overall polarity of molecule, leading to gain in solvation energy
63
Q

How does fluorination modulate binding efficiency and bioavailability in serotonin receptor ligands?

A
  • w/ no Fs –> IC50 and EC50 low, pKa 100:1 and v low bioavailability
  • adding 1 F makes binding to target a bit worse, but improves bioavailability, so can now get into bloodstream
  • adding 2 Fs decreases pKa, but IC50 too high and now has 2 biological effect
  • so adding 1 F is optimal
64
Q

How is distribution an important property of drugs to consider?

A
  • many compounds (hydrophobic and others) not soluble in bloodstream
  • carried round body by human serum albumin (HSA), which has a no. of hydrophobic binding pockets
  • want compounds to be in free state, so can be released when reach target (fluoridation can modulate binding of ligand to HSA)
65
Q

How can distribution of drug be tracked through the body?

A
  • positron emission tomography (PET)

- use radioactive 18F isotope

66
Q

What is the major problem w/ metabolism for drug candidates?

A
  • xenobiotic compounds (foreign to host) metabolised before excretion
67
Q

What are the 2 phases of xenobiotic metabolism?

A
  • phase 1 = oxidation

- phase 2 = conjugation

68
Q

How does phase 1 of xenobiotic metabolism occur in ibuprofen (what half reactions occur)?

A
  • DIAG*
  • R-H + H2O R-OH + 2H+ + 2e- (OX)
  • NADPH NADP+ + H+ + 2e- (RED)
  • O2 + 4H+ + 4e- 2H2O (OX)
69
Q

What is the purpose of oxidation in xenobiotic metabolism?

A
  • makes molecules more able to undergo addition reactions
70
Q

What is the role of P450 isozymes, and how many are there?

A
  • cat hydroxylation reactions in liver
  • interconversion of FeII / FeIII (OX + RED)
  • human genome encodes >50 diff P450 isozymes
71
Q

What is the role of conjugation in xenobiotic metabolism, and when does it occur?

A
  • adds lots more polar quality so can’t get across membrane anymore
  • often occurs after ox has added functional group to drug
72
Q

What is the effect of fluoridation on metabolism?

A
  • fluoridation can mod metabolism
  • C-F bond stronger than C-H
  • ox of C-F by cytochrome P450 more difficult
  • metabolism reduced, so bioavailability increased
73
Q

What is the 1st pathway for excretion of drugs?

A
  • drugs absorbed in kidneys and excreted in urine
  • blood filtered by glomeruli (capillaries)
  • compounds <60kDa pass through
  • glucose, nts, water etc. and some drugs reabsorbed
  • other compounds excreted
74
Q

What is the 2nd pathway for excretion of drugs - enterohepatic cycle?

A
  • compounds that avoid filtration in kidneys can be actively transported into bile and then intestine
  • further metabolism can occur (excreted in stool) or drug reabsorbed to enter circulation
  • decreases rate of excretion of drug
75
Q

How can excretion kinetics be calc?

A
  • often complex, but sometimes fixed % removed over given period = exponential loss
  • [L]0 / 2 = [L] t1/2
  • may not be exactly exponential
76
Q

How can drug toxicity limit drug effectiveness?

A
  • modulate target too effectively –> can stop activity of target completely, good for pathogen, but may not be good for signalling molecule etc.
  • off target effects in same family
  • off target effects in diff family –> commonly drugs bind to hERG K+ channel, which stops heart if blocked, so all drugs tested for this
  • toxic metabolic byproducts
77
Q

What is the problem w/ taking high doses of paracetamol, and how is it treated?

A
  • DIAG*
  • liver glutathione drops dramatically
  • left w/ highly toxic N-acetyl-p-benzoquinone imine
  • treatment is N-acetyl cysteine –> promotes biosynthesis of glutathione so imine can be converted
78
Q

What is the lethal dose (LD50), and what is iit comparable to?

A
  • amount req to kill half animals in test

- comparable to EC50 (effective dose)

79
Q

How is therapeutic index calc, and what value is wanted?

A
  • LD50 / EC50

- want high no. –> indicates big diff between effective and lethal dose

80
Q

What are diff methods of drug discovery?

A
  • serendipity
  • screening
  • design
81
Q

How did penicillin become an available drug, and why does it not have the best ADME properties?

A
  • Fleming observed it killed S. aureus
  • beta lactam, inhibits transpeptidase of peptidoglycan
  • Pain 2st to use it to treat patients
  • Florey and Chain synthesised it to powdered molecule
  • only 20% absorbed, 80% excreted in urine, so used to extract it from patients urine when levels low
82
Q

How is Aspirin an eg. of designing a drug via screening?

A
  • salicylic acid extracted from willow bark
  • Hoffman screened for derivatives
  • acetylated it –> acetylsalicylic acid = less irritating and more effective
  • inhibits prostaglandin synthesis
83
Q

How do HIV proteases work?

A
  • DIAG*
  • break peptide bond, by activating water molecule to attack it
  • forming tetrahedral intermediate
84
Q

How was making HIV protease inhibitors an eg. of structure based design?

A
  • 1 part soluble w/ low activity and other low solubility but high activity
  • when joined together they are like transition state analog
  • used knowledge of structure of protein and compounds identified by screening
85
Q

How was mod of HIV protease inhibitor poss?

A
  • structure showed poss at 1 position, as adding groups here doesn’t affect binding of drug to protein as out of way and coming out into solvent –> adding pyrimidine derivative best (IC50 not as good as others tried, but much higher serum conc so EC50 much better, and good solubility halfway between hydrophobic and hydrophilic)
  • can aromatise ring to get active form of Crixivan
86
Q

What are the main steps to designing a new drug?

A
  • identify target
  • design/screen for lead compound
  • improve bioavailability/efficacy (ADME) and toxixcity
87
Q

What potential targets are there for drugs?

A
  • KO essential genes in pathogens
  • pot targets in human genome
  • -> 500 kinase genes
  • -> 800 7 TM receptors (350 odorant receptors) = GPCRs
  • -> changes in gene expression, protein localisation, PTM from diseased organisms
  • -> gene expression in particular tissues or cell types
88
Q

What is an eg. of how genetic diffs can modulate drug efficacy?

A
  • beta blockers acting on beta-1-adrenergic receptor for hypertension
  • get allelic variation of 2 crucial residues, S49 and R389
  • -> G49/R389
  • -> S49/G389
  • DIAG*
  • SR/SR = greatest reduction in blood pressure
  • SR/GR = 1 mutation, so 1 pair not as good, but still works
  • SR/SG = even worse mutation
  • GR/SG = doesn’t work at all
89
Q

Why are most drugs today tested on young males, and why might this be a problem?

A
  • risk young females pregnant or could affect future children –> so less ethical
  • but wrong to assume men and women have exactly same metabolism, so drug may be more/less effective
90
Q

How do you design a lead compound?

A
  • use biochem knowledge for 1st inhibitor
  • enzyme target –> substrate or transition state mimic
  • receptor target –> natural ligand mimic or monoclonal antibody (eg. prevent dimerisation in signal transduction)
  • natural substrate/ligand conc will affect drug potency
91
Q

What can combinatorial chem produce for screening a lead compound?

A
  • large libraries (millions) of compounds
92
Q

What is the problem w/ using screens to get large libraries of compounds?

A
  • approx 10^40 poss compounds w/ mw <750
  • can’t make all, so limited possibilities investigated
  • eg. if add phosphate in 1 position, can’t add anything else there, and carry on w/ that molecule, so missed out on lots of chem
93
Q

How is a screen for a lead compound carried out to create a large library?

A
  • bind compound to agarose beads (substrate)
  • add 1st reactant set –> one to each set of components
  • pool
  • add 2nd reactant set and repeat
94
Q

What are the diff steps in designing a new drug and getting it to clinical use?

A
  • preclinical drug discovery (v expensive)
  • phase I –> safety, tested on healthy people
  • phase II –> safety, efficacy, dosage, on patients
  • phase III –> safety, efficacy, dosage, on patients but bigger scale
  • phase IV –> low freq side effects, double blind trials

MBB261 (6 decks)

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