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CfP 2 > Toxicology & Lead Generation > Flashcards

Toxicology & Lead Generation Flashcards

1
Q

What are the 4 ways to discover a new drug?

A
  • Follow-on compounds
  • computational modelling and sequencing
  • serendipitous discovery
  • evergreening
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2
Q

What are follow-on compounds?

A
  • new indication discovered
  • need to get lucky for this to happen
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3
Q

What is computational modelling and sequencing?

A
  • increasing number of solved protein x-ray crystal structures
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4
Q

What is serendepitous discovery?

A
  • same mechanism as previously reported drug
  • “fast followers” or “me too” drugs
  • provide professionals and patients with options, keep prices low and comes with a degree of reassurance
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5
Q

What is evergreening?

A
  • extreme form of a “me too” drug
  • requires an in depth knowledge of medicinal discovery
  • extending the duration of a patent with minimal chemical intervation
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6
Q

What is target validation?

A
  • first step
  • exploring relationship between pharmacological modulation of a target and a pathological condition
  • what are you trying to achieve?
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7
Q

What is hit identification?

A
  • second step
  • finding a chemically accessible (able to be synthesised easily) compound displaying an initial activity towards a target
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8
Q

What characteristics does a compound have for hit identification?

A
  • small organic molecule
  • moderate affinity
  • low MW (150 < 400)
  • c Log P < 4.5
  • 1-4 rings
  • < 8 H bond acceptors
  • < 5 H bond donors
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9
Q

What is rational design?

A
  • based on physiological binders (substrates, co-factors) gives us idea of shape as it binds to target of interest already
  • utilises structural info to improve ligand interactions in binding site
  • smaller less complex molecules with a smaller number of functional groups and tend to rule of 3
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10
Q

What is the rule of 3?

A
  • MW < 300
  • cLogP <= 3
  • HBDs <= 3
  • HBAs <= 3
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11
Q

What is high throughput screening?

A
  • if you don’t know much about your target rational design isnt useful
  • screen as many compounds and hope
  • high number of sp2 centres = general flat nature
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12
Q

What are the two types of high-throughput screening?

A
  • unselected screens
    • hit rates ~ 1%
    • screen millions of compounds to get a decent number of hit families to follow up
    • limited by budget, time, rescources and intrinsic throughput
    • limited to a number of compounds at a single concentration
    • generates noise (false positives or negatives)
  • selected screens
    • enough info about target to inform screening
    • combination of rational design and unselected screening
    • greatly increases speed, reduces costs and makes identification easier
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13
Q

How can you recognise natural compounds?

A
  • high number of stereocentres and complex structure
  • lots of fused-ring systems
  • macrocycles
  • presence of a number of basic Nitrogen atoms (alkaloids)
  • chemical produced by organism
  • trying to control synthesis is difficult
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14
Q

What are PAINs?

A

pan-assay interference compounds (PAINs)

  • positive hit compounds which turned out to be due non-specific binding
  • defined structures, containing several chemical classes
  • time and research money wasted
  • known PAINs bearing known troublesome chemical groups which have non-specific binding/false positives (eg quinones) are filtered out before screening
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15
Q

Why shouldnt you excludes PAINs completely?

A

structures can be important in final molecules

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16
Q

What is the rule of 3 derived from?

A

Lipinski’s rule of 5

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17
Q

What is fragment screening?

A

method of reducing ligand complexity to increase rhe chance of a match with target site

samples chemical space at finer resolution

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18
Q

What are prerequisites before starting a hit-2-lead campaign?

A
  • chemically acceptable
    • can you do this chemistry on scale?
  • starting hit responds to chemical modulation, quantifiable SAR
  • freedom to operate
  • preliminary ADME profile looks favourable
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19
Q

What can be a limiting factor in absorption?

A

low water solubility/high lipophilicity

20
Q

How can you prevent a molecule from passing BBB?

A

modulate pKa by changing functional groups

decrease pKa

21
Q

What are the 4 strategies for optimisation?

A
  • homologation
  • disjunction
  • conformational constraining
  • biostere substitution
22
Q

What is homologation?

A
  • a homologous series is a group of compounds that differ by a constant unit
  • idenity SARs (affinity, selectivity, solubility, half-life)
23
Q

What is disjunction?

A
  • identify minimal structure associated with activity at sought target and remove rest
  • good for natural products
24
Q

What is conformational constraining?

A
  • ‘freeze’ drug in particular conformation to best suit target
  • ideal conformation - bioactive conformation - can be determine by trial and error/rational
25
Q

What is biostere substitution?

A

substituents that have chemical or physical similarities and related molecular shapes

  • structural: geometry, size, shape, polarizabilitiy, hydrogen bonding
  • receptor interaction: all parameteres (except lipid/water solubility)
  • pharmacokinetics: lipophilicity, pKa, hydrogen bonding
  • metabolism: metabolic reactivity

most common change: COOH to imedazole

26
Q

What causes drug toxicity?

A
  • tagret driven
  • idiosyncratic toxicity
  • drug interactions
  • generation of reactive metabolites
  • carcinogenicity
  • other causes
27
Q

What are enthalpic (increasing energy) interactions?

A
  • loss of ligand-water bonding
  • loss of protein-water bonding
28
Q

What are enthalpic (decreasing energy) interactions?

A
  • formation of bonding interactions
  • energetic changes in protein or ligand
29
Q

What are entropic (increasing energy) interactions?

A
  • loss of conformational flexibility in protein
  • loss of conformational flexibility in ligand
30
Q

What are entropic (decreasing energy) interactions?

A
  • desolvation of ligands
  • return of bound water to bulk state
31
Q

Describe hydrophilic ligands.

A
  • bind predominantly through bonding interactions
    • enthalpic
  • enthalpic - increasing energy (endothermic)
    • loss of ligand-water bonding interactions
  • enthalpic - decreasing energy (exothermic)
    • formation of bonding interactions with protein (target)
32
Q

Describe lipophilic ligands.

A
  • bind predominantly through entropic effects
  • interaction is less specific
  • enthalpic - endothermic
    • loss of protein-water bonding interactions
    • energetic changes in protein/ligand
  • enthalpic - exothermic
    • energetic changes in protein or ligand
  • entropic - endothermic
    • loss of conformational flexibility in protein
    • loss of conformation flexibility in ligand
  • entropic - exothermic
    • desolvation of ligands
    • return of bound water to bulk state
33
Q

What is considered secondary pharmacology?

A

biological target or effect which is not linked to its efficacy

34
Q

What are the mechanisms of phase I metabolism?

A
  • oxidation
    • aliphatic or aromatic hydroxylation
    • N/S oxidation
    • N/O/S delkylation
  • reduction
    • nitro group into hydroxylamine or amine
    • carbonyl into alcohol
  • hydrolysis
    • ester, amide or phosphate into coressponding acid and alcohol/amine
    • hydrazides into acid and substituted hydrazine
35
Q

What is the main class of protein involved in phase I metabolism and what does it carry out?

A

cytochrome P450s

carry out oxidation in liver cells

also found in liver cells

36
Q

What is the rate of oxidation determined by?

A

stereo-electronics of the oxidation and the concentrations

how available are electrons to form and break bonds?

37
Q

Why are more lipophilic drugs likely to be more rapidly cleared?

A

more driven by entropic factors

dissociation constant’s consistent effects are the solvent based (entropic) factors

38
Q

What is F% formula and what does it mean for a more lipophilic molecule?

A

F% = Fabs x Fprehepatic x Fhepatic

more lipophilic:

  • less hepatic clearance as its been metabolised already
  • less Fabs due to low solubility
39
Q

What is the most common cause of drug-drug interaction?

A
  • taking a drug that is an inhibitor of CYP enzymes - binds to metal centre
  • unhindered aromatic nitrogen atoms are likely to be CYP inhibitors as N lone pair is good at co-ordinating to iron
  • exposure increases of other drug due to decreased metabolism
40
Q

What are the two approaches to avoid reactive metabolites?

A
  • exclude chemical functionalities undergoing metabolic activation
  • screen for reactive metabolite formation (RM Assays)
41
Q

What are the mechanisms of phase II metabolism?

A
  • glucuronidation
    • seen in carboxylic acid, alcohols, phenols and amines
    • mr of 194
    • can lead to idiosyncratic toxicity
  • sulphation
    • alcohols, phenols, amines
    • mr 70/80
  • glutathione (GSH) conjugation
    • halogenated compounds, epoxides, arene oxides, quinone-imines, DNA
    • mr 312
42
Q

What is type b toxicity?

A
  • idiosyncratic toxicity
  • levels of glucuronide may be high or they develop an extreme immune response to low levels of alkylated proteins, leading to serious liver injury
43
Q

What is the role of GSH conjugation in paracetamol?

A
  • paracetamol forms NAPQI after phase I
    • phenol alcohol group oxidised to ketone
  • this is an active metabolite
  • phase II is GSH conjugation
  • if GSH levels depleted, NAPQI levels accumulate, leading to non-specific alkylation of proteins in liver
    • proteins seen as foreign to immune system
    • inflammatory response and cell damage
44
Q

What is the purpose for mutagenicity models and give an example?

A

eg Ames Assay

opportunity to highlight drugs that may show particularly high mutagenicity

amines are likely to give a fale positive result

45
Q

Why can mutagenicity often be attributed to the presence of a masked aromatic amine?

A

amines may exist as part of an amide bond thats hydrolysed as part of phase I metabolism

CfP 2 (4 decks)

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