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CHEM20421 > Drug Discovery > Flashcards

Drug Discovery Flashcards

1
Q

History of medicinal chemistry – Emergence of Homo sapiens

A
  • Earth formation: 4.5bya
  • First prokaryotes: 3.5bya
  • Multicellular structures: 2.8bya
  • First eukaryotes: 2bya (first fossils found were red algae, 1.2bya)
  • Oxidation of atmosphere begins: 2bya
  • Fish: 530mya
  • Mammals: 200mya
  • Homo sapiens: 200,000 years ago (0.004% of Earth history)
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2
Q

History of medicinal chemistry – Morphine

A
  • Isolated 1800, commercial production 1833
  • Potent analgesic. Still in use.
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3
Q

History of medicinal chemistry – Anaesthetics

A
  • Introduced 1840s. Vastly improved surgical outcomes.
  • Diethyl ether (poor side effects, highly flammable) and chloroform (causes arrhythmia, narcosis) have fallen out of use.
  • Nitrous oxide is still used in childbirth, dentistry and trauma cases.
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4
Q

History of medicinal chemistry – Salvarsan

A
  • First synthetic drug, released 1910. Treated syphilis.
  • Became most widely prescribed drug in the world (2m doses produced annually in US by 1920).
  • Originally thought to be a double bonded dimer, later found to be a mixture of trimer and pentamer.
  • Neutral form is highly sensitive to oxidation and active form generated by in situ oxidation.
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5
Q

History of medicinal chemistry – Penicillin

A
  • Isolated in 1928. Large quantities used in WWII to treat wounded soldiers.

β-lactams have significant tortional strain. The C-N bond is distorted so attractive for cleavage.
N/O are electronegative, making the carbonyl carbon significantly electrophilic.

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6
Q

Drug discovery

A

The search for new or improved agents for treating human disease.

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7
Q

Drug discovery - Lead driven approach

A

Natural/ synthetic compounds screened for effects on microorganisms, cell lines, enzymes or tissues.

Fairly “hit-and-miss” and relies on rapid screening as many compounds as possible to be viable.

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8
Q

Drug discovery - Target driven approach

A

Molecular mechanisms involved in a disease state are derived and a strategic target selected.

Potential molecules are rationally designed to interact with the target.

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9
Q

Drug discovery - Hit compound

A

A compound that displays a pre-determined threshold level of activity against target.

Compounds for screening may be synthetic or natural products, may come from compound libraries, and can be informed by underlying knowledge of target (eg. shapes of endogenous signallers).

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10
Q

Drug discovery - Lead compound

A

A reproducible hit on the primary screen with a structure amenable to modification to improve pharmaceutical ability.

Very few hit compounds become lead compounds.

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11
Q

Drug discovery - Lead compound criteria

A
  • Potency – amount required to achieve desired biological effect. Potency quantified using a dose-response curve, generated from effect at different concentrations. Eg. for enzymes, IC50 (concn required to reduce enzyme activity by 50%) often used.
  • Efficacy – other assays (eg. cell-based) used to verify the drug can reach target in living systems and induce a phenotypic (functional) response.
  • Tractability – suitability for chemical modification to allow analogues with more drug-like properties.
  • Availability – ease and cost of synthesis, considering eventual large-scale preparation.
  • Patentability – IP rights assessed on databases.
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12
Q

Drug discovery - Lead optimisation

A

Compound displaying target activity & lead requirements is modified to improve pharmacological properties. Modified structures are synthesised and bioassays repeated. Important considerations:

  • Does biological activity transfer to animal/human models?
  • Is compound toxic?
  • Is compound absorbed by tissues other than its target? (eg. Viagra & eyes)
  • Is compound sufficiently orally bioavailable?
  • How quickly is compound metabolised?
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13
Q

Drug discovery - Considerations affecting bioavailability

A
  • Absorption – in vivo studies of absorption characteristics required.
  • Distribution – once absorbed, drug will be distributed (usually via bloodstream). Characteristics of distribution depends on route of administration, formulation, properties.
  • Metabolism – drugs metabolised to facilitate clearance (mostly in liver). Metabolites may be pharmacologically active or inactive and can be determined in in vivo studies.
  • Excretion – metabolites are eliminated (eg. urine, faeces, exhalation). Characteristics must be determined (using in vivo studies).

Modifying structure to improve bioavailability is challenging.

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14
Q

Drug discovery - Lipinski’s Rules

A

Optimising for oral bioavailability:

  • Molecular weight < 500 Au / g mol-1
  • Calculated logP < 5
  • Hydrogen bond donors < 5
  • Hydrogen bond acceptors < 10
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15
Q

Drug discovery - Preclinical development

A

Study of how drug candidates interact with targets, in vivo & in vitro.

Pharmacokinetics, pharmacodynamics, toxicology

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16
Q

Drug discovery - Pharmacokinetics

A

Strength of response determined by concentration in active site. Drug must reach target with sufficient concentration for sufficient duration for useful response.

Influences: administration, absorption efficiency, rate of transport, metabolism/ excretion etc.

Determining factors influencing concentration-time course of a drug in varying bodily fluids.

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17
Q

Drug discovery - Pharmacodynamics

A

Study of the observable pharmacological effect the drug has on an organism.

Includes pharmacological response, duration/ magnitude of response relative to concentration at active site.

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18
Q

Drug discovery - Toxicology

A

Most potent drugs are dose-limited by side effects in human patients.
Therapeutic ratio must be established.

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19
Q

Drug discovery - Process chemistry

A

Developing a robust, reliable and economical large-scale synthesis.
Suitable candidates must be synthesised on a kg scale for clinical trials.

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20
Q

Drug discovery - Formulation studies

A

Confirming drug can be presented in a suitable form for administration.
Also confirming drug has a long-shelf life and is stable to heat, light or moisture.

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21
Q

Drug discovery - Phase 1 clinical trials

A
  • Small group trials (<1 year) on healthy participants (30-100).
  • Determines safety, tolerability, human pharmacokinetics and dosage.
  • 1 in 2500 lead compounds achieve clinical trial stage.
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22
Q

Drug discovery - Phase 2 clinical trials

A
  • Small group trials (2-3 years) on affected patients (100-300).
  • Determines efficacy in target population, also side effects.
  • Patients usually undertake double blind placebo studies to determine efficacy.
  • Drug completes phase if it out-performs placebo and long-term side effects are negligible.
23
Q

Drug discovery - Phase 3 clinical trials

A
  • Large group trials (3 years or more) on affected patients (usually up to 5k).
  • Can show efficacy compared to other drugs on the market. Also can show rare side effects not apparent in smaller population sizes.
24
Q

Drug discovery - Phase 4 clinical trials

A
  • Post-release.
  • Efficacy and side effects continue to be monitored once on the market.
25
Q

Amino acids - Glycine

A
  • Hydrophobic
  • Gly, G
26
Q

Amino acids - Alanine

A
  • Hydrophobic
  • Ala, A
27
Q

Amino acids - Valine

A
  • Hydrophobic
  • Val, V
28
Q

Amino acids - Leucine

A
  • Hydrophobic
  • Leu, L
29
Q

Amino acids - Isoleucine

A
  • Hydrophobic
  • Ile, I
30
Q

Amino acids - Proline

A
  • Hydrophobic
  • Pro, P
31
Q

Amino acids - Phenylalanine

A
  • Aromatic
  • Phe, F
32
Q

Amino acids - Tyrosine

A
  • Aromatic
  • Tyr, Y
  • pKa = 10.1
33
Q

Amino acids - Tryptophan

A
  • Aromatic
  • Trp, W
34
Q

Amino acids - Serine

A
  • Alcohol-containing
  • Ser, S
35
Q

Amino acids - Threonine

A
  • Alcohol-containing
  • Thr, T
36
Q

Amino acids - Cysteine

A
  • Sulfur-containing
  • Cys, C
  • pKa = 8.3
37
Q

Amino acids - Methionine

A
  • Sulfur-containing
  • Met, M
38
Q

Amino acids - Aspartic acid

A
  • Acidic
  • Asp, D
  • pKa = 3.9
39
Q

Amino acids - Glutamic acid

A
  • Acidic
  • Glu, E
  • pKa = 4.2
40
Q

Amino acids - Asparagine

A
  • Amidic
  • Asn, N
41
Q

Amino acids - Glutamine

A
  • Amidic
  • Gln, Q
42
Q

Amino acids - Histidine

A
  • Basic
  • His, H
  • pKa = 6
43
Q

Amino acids - Lysine

A
  • Basic
  • Lys, K
  • pKa = 10.8
44
Q

Amino acids - Arginine

A
  • Basic
  • Arg, R
  • pKa = 12.5
45
Q

Protein

A

High molecular weight (>10 kDa) polymers of α-amino acids with multiple biochemical roles

46
Q

Proteins - Roles

A
  • Hormones (regulation, messengers)
  • Enzymes (catalysts)
  • Receptors (produces cellular response from external triggers)
  • Protective proteins (antibodies, complement etc)
  • Transport (transporting substances across bilipid membranes)
47
Q

Proteins - Isoelectric point

A

The pH at which the amino acids is neutral / the zwitterion is present = the average of the pKas that involve the zwitterion.

48
Q

Proteins - Primary structure

A

Amino acids condense between amino group & carboxylic acid group. Free ends can extend.

Oligopeptide = a few aas. Polypeptide = many aas.

49
Q

Proteins - Polymer of unique amino acids

A

Polymer of n amino acids, using each once, has n! variations

50
Q

Proteins - Polymer of unspecified amino acids

A

Polymer of x residue length, using any of n amino acids, has xn variations

51
Q

Proteins - Secondary structure factors

A
  • Stereochemistry of amide link (dihedral angle) – lp of amide N can enter resonance with carbonyl. Structure has significant sp2 character so reduced rotation.
  • Hydrogen bonding – carbonyl oxygen & amide hydrogen have partial charges & can form inter- or intra-chain hydrogen bonds.
52
Q

Proteins - α-helix

A

Produced by coiling backbone to H-bond C=O of residue n to NH of residue n+4.

All backbone C=O/NH participate. All side chains point outward.

53
Q

Proteins - β-pleated sheet

A

Produced by fully extending backbone. Sheets run parallel or antiparallel.
Antiparallel has less distorted C=O‐‐‐N-H bonds.

Side chains alternate sides of sheet to minimise sterics.

54
Q

Proteins - β-turn

A

Changes direction of backbone. H-bond between C=O of residue n & NH of residue n+3.

Proline has no NH to bond with so is often found in turns.

CHEM20421 (2 decks)

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