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med chem Flashcards

1
Q

What does SAR stand for?

A

structure activity relationship

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2
Q

How are SARs usually determined?

A

by making minor changes to the structure of the hit and assessing the effect that this has on a suitable biological activity assay

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3
Q

How are changes to the hit for SARs classified?

A

the size and shape of the carbon skeleton, the nature and degree of substitution, and the stereochemistry of the lead

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4
Q

Three ways the shapes and sizes of molecules can be modified?

A
  • changing the number of methylene groups in chains and rings
  • increasing or decreasing the degree of unsaturation
  • introducing or removing a ring system
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5
Q

How does changing the number of methylene groups in a chain affect the shape and size of the molecule?

A

incr in no. increases the size and lipophilicity of the lead compound, incr lipophilicity = incr activity due to higher membrane penetration

decr activity is likely due to the new more lipophilic molecules (more methylenes) are poorly water soluble so poor distribution and trapping of the analogue in membranes

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6
Q

How can changing the degree of unsaturation affect drug activity?

A
  • increasing saturation can give loss of activity if the molecule interacts by being electrophilic
  • increasing unsaturation can change geometry which may give a higher affinity for the receptor
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7
Q

How can the addition/removal of a ring system affect drug activity?

A
  • introduction of a ring increases the size of the molecule, if there’s an increase in activity with the ring added, could be due to occupying an additional hydrophobic pocket
  • removal of a fused ring in morphine can give less addictive properties
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8
Q

How is a trans double bond significant in reactions?

A

can oxidise things v quickly

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9
Q

Why are double bonds avoided in SAR?

A

the group has potential to form epoxides and other chemically reactive metabolites, often cyclopropane (triangle) is used instead of the double bond

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10
Q

How does introducing new methyl group substituents affect the SAR?

A
  • increased lipophilicity and reduced water solubility

- can produce steric hindrance to block metabolism if adjacent to an aromatic substituent

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11
Q

What is the partition co-efficient?

A

the hydrophobic character of a drug measured experimentally in an octanol/water mixture, more lipophilic drugs have a higher partition coefficient (P)

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12
Q

Equation for the partition coefficient?

A

conc of drug in octanol/conc of drug in aq solution

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13
Q

What is the effect of chlorine substitution?

A

to increase lipophilicity (more than a methyl group), can also have a steric effect

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14
Q

How does substitution of a hydroxyl group affect a molecule?

A

incr water solubility, gives new site of H bonding w a receptor, gives site for phase 2 metabolism = can shorten a lipophilic drug’s half life

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15
Q

Why should the number of basic groups present in a drug be limited?

A

if the drug molecule is too highly charged it will not pass across biological membranes e.g amines

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16
Q

Why should aromatic amines be avoided in drug molecules?

A

can be metabolised to toxic metabolites

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17
Q

What does introduction of acids into a lead structure do?

A

increases water solubility e.g. carboxylic acid

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18
Q

What are isoteres?

A

groups that exhibit some similarities in their chemical and physical properties e.g. F can replace H as it is small

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19
Q

What are bioisosteres?

A

groups that exhibit some similarities in their chemical and physical properties, with similar biological activity

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20
Q

In development of B-1 antagonists what is the original molecule in the case study and what is the final developed drug?

A 
isoprenaline = original
propranolol = final
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21
Q

How was isoprenaline developed into propranolol (initial stage)?

A
  • Isosteric replacement of hydroxyl groups in isoprenaline with Cl to form dichloroisoprenaline (DCI)
  • replacing the Cl ring with a double aromatic ring to form pronethalol
  • extending the molecule by adding a CH2O (single O) to the end of the OH chain (where was connected to the aromatic rings) and attaching the new O in position 1 of the aromatic ring
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22
Q

What is the structure of isoprenaline?

A

benzene ring with 2(OH) in positions 5 and 6, in position 2: CHOH-CH2-NH-(2CH3)

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23
Q

What are the SARs for propranolol?

A

substitution lowers activity, alpha chirality of the OH is essential for H-bonding interactions, the lone O is involved in H-bonding to the receptor, branching of the 2(Me) is beneficial to the hydrophobic pocket

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24
Q

What type of molecule is isoprenaline?

A

selective beta agonist to B1

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25
What type of molecule is propranolol?
non-selective beta antagonist (B1 and B2)
26
Why is fluorine often used as a substituent?
- the C-F bond is relatively inert to metabolic cleavage - F has a larger vdw radius than H so it doesn't exert steric hindrance at receptor sites - F can act as a HBA and is similar in strength to C-O bond - increases lipophilicity and facilitates hydrophobic interactions with enzymes or at receptor sites (increases logP) - can prevent oxidation of aminophenols to quinoneimines
27
What does a higher value of oxidation potential mean?
a more stable analogue, more fluorine substitution = more stable
28
Describe the reaction mechanism for the metabolism of paracetamol after a normal dose
P-450 enzyme catalyses the reaction, GSH attacks one of the ring's double bonds and the ed transfers to the =N and away so there is no charge on anything, the GS substitutes in either position 2 or 6
29
What is the structure of paracetamol?
benzene ring with OH at the top and NHCOCH3 at the bottom
30
Describe the reaction mechanism for the metabolism of paracetamol after an overdose
when there's an overdose glutathione is depleted in the liver and GSH can't attack the double bond, so the paracetamol binds to cellular macromolecules and causes hepatotoxicity, causing liver damage
31
How was atenolol developed from propranolol?
the double aromatic ring was swapped to a single benzene with HN-=O-CH3 at the bottom (with the O still at the top) to form practolol (B1 selective) the NH was then removed and replaced with CH2, and the NH2 replacing the end of the =O-CH3 to form atenolol
32
Why is paracetamol not toxic with a normal dose?
even though a small amount is still oxidised in the liver, the liver is protected by glutathione which detoxifies the reactive quinoneimine by conjugate addition
33
In what order must you carry out reactions to fluorine substituted molecules?
``` nitration in position 3 (HNO3 & H2SO4), acylation in position 1 -replaces F- (OCH3- & Na+), reduction of NO2 to NH2 (NaBH4), addition of COCH3 to NH2, demethylation (BBr3) ```
34
What is the SAR for atenolol?
additional hydrogen bonding at the bottom =O is key, hydrophobic interactions from the benzene, additional H bonding gives selectivity
35
What are the pharmacodynamics of fluorine substitution?
- increase in lipophilicity - increase in T1/2 (the time for plasma conc of drug to drop by 50%) - isosteric replacement of OH or H - similar vdw radius to H so no steric effects
36
How can fluorine substitution improve drug metabolism and toxicity?
incorporating F at sites of hydroxylation, if reactive metabolites are formed examine the effect of F on stabilising the lead compound
37
How is biological activity often quantified?
log 1/C
38
When plotting log P what do you plot on each axis and what is the equation of the line?
activity on y axis (log 1/C), physicochemical property on the x axis (log P), equation of line: y = (k_1)*logP + k_2
39
What does increasing log P show?
increasing lipophilicity
40
What is a QSAR study like?
- involves a single systemic variation at a specific position on an aromatic ring, keeping all substituents constant - the influence of chemical substitution on hydrophobic, electronic, and steric properties is examined
41
What happens if lipophilicity is increased too much?
may make the drug too hydrophobic so activity may be decreased by: poor absorption, trapping in fat deposits, higher susceptibility to drug metabolism
42
What is log Po?
optimum logP
43
What is the substituent hydrophobicity constant (pi)?
a measure of how hydrophobic a substituent is relative to hydrogen
44
What is the equation for the hydrophobicity constant?
pi_x = LogP_x - LogP_H
45
What is P_H (subscript H)?
the partition coefficient for the standard compound (benzene)
46
What is P_x (subscript x)?
the partition coefficient for the standard compound with the substituent
47
What is the logP value for benzene?
2.13
48
What does a positive hydrophobicity constant mean?
that the substituent makes the standard molecule more hydrophobic (e.g. could be due to binding well to a hydrophobic binding pocket)
49
What does a negative hydrophobicity constant mean?
the substituent is extremely polar - much more water soluble due to hydrogen bonding
50
How are LogP and pi different?
``` LogP = the drug's overall hydrophobicity pi = the hydrophobicity of a particular region on a candidate drug molecule ```
51
What is the Hammett substitution constant (sigma)?
the electron withdrawing or donating ability of a substituent, an EWG gives a higher value (sigma is positive), EDG gives a lower value (sigma is negative)
52
What's the equation for the Hammett constant?
sigma_x = LogK_x / K_H = LogK_x - LogK_H
53
What is K_H?
indicates that the benzoic acid derviative is unsubstituted -ionised- (only has H)
54
What is the Hammett substitution constant for hydrogen?
zero
55
Why are functional groups not on the ortho position of the aromatic ring for Hammett substitution constants (w/ benzoic acid)?
ortho groups have too much steric hindrance with COOH
56
What are the two steric effects?
Taft Steric Parameter (Es), and Molar refractivity (MR)
57
What is molar refractivity?
the volume occupied by a compound and how easy it is to polarise
58
What is the Hansch equation?
Log(1/C) = (K_1)LogP + K_2(sigma) + K_3Es + K_4
59
What is LE and its equation?
Ligand Efficiency = Gibbs free energy of binding per non-hydrogen (heavy atom) = how efficient the ligand is at binding (irrelevant ligands can be excluded so the compound isn't unnecessarily large
60
Equation for LE
LE = -(change in G)/HA or LE = 1.4 (-logIC50)/HA HA = number of heavy atoms/anything not H
61
What is LLE?
Lipophilic Ligand Efficiency (aka LiPE) = difference between p(activity) and lipophilicity (cLogP or LogD)
62
Equation for LLE
LLE = pIC50 - cLogP
63
What is cLogP?
the predicted LogP by the computer
64
What is LogD?
same as LogP but instead of the drug being in its unionised form, with LogD the drug is a mixture of its ionised and unionised form
65
What is IC50?
Measure of the potency of a substance in inhibiting a specific biological or biochemical function by 50%, typically expressed as a molar concentration = halfway between maximal and minimal inhibition
66
What is pIC50?
the negative log10 of the IC50 value when molar
67
What is the optimum LLE for a good drug candidate?
LLE must be bigger than 5
68
What is the optimum LE for a good drug candidate?
LE must be bigger than 0.3
69
What is the optimum cLogP for a good drug candidate?
cLogP must be smaller than 3
70
What is group efficiency (GE)?
extension of LE, estimates the binding efficiency of parts of a molecule or groups added to an existing lead
71
What is enthalpic efficiency (EE)?
uses (change in H) instead of (change in G)
72
What is Lipophilicity-corrected ligand efficiency (LELP)?
LogP/ligand efficiency
73
What is size-independent ligand efficiency (SILE)?
a way to identify compounds with a high LE across a wide range of ligand sizes and to track their progress during the drug design process
74
What is Astex ligand lipophilicity efficiency (LLEAT)?
doesn't include non-specific binding
75
What is Property Forecast Index (PFI)?
based on lipophilicity being minimised and most drugs only containing a few aromatic rings, is predictive of solubility
76
How is high throughput screening (HTS) different to FBDD?
HTS screens for one hit compound that fits all of the active sites, FBDD uses a fragment library and fragment linkage to form the drug
77
Advantages of FBDD?
- fragment libraries are of good quality which is less likely with HTS - fragments can be grown with drug-likeness in mind (many HTS compounds can't be optimised) - huge libraries not required to find hits - Fragments detect allosteric binding sites or create new binding pockets that larger molecules wouldn't
78
Disadvantages of FBDD?
- use of small generic fragments - other labs may find similar hits - tend to start with efficient binders rather than tight binders - limits methods used for detection of hits - sensitive detection methods are required - some sensitive detection methods are expensive in time and money
79
What are the 5 steps of FBDD?
- fragment library design - core fragment generation - fragment growing - activity evaluation for new hits - new candidate selection

CHEM248 (3 decks)

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