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Patho 2023 > Medicinal Chemistry (EXAM 1) > Flashcards

Medicinal Chemistry (EXAM 1) Flashcards

1
Q

how do you modulate biological activity of the drug?

A
  1. binding to the receptor
  2. moving to the location where the receptor is present
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2
Q

what is a drug?

A

a drug is any substance that brings a change in biologic function through its chemical actions

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3
Q

how are structure and activity correlated?

A

structure determines activity
- the properties of the drugs depend on the chemical constituents of the molecule
- when you modify the structure, you change the property
- when you examine the structure, you can predict the properties

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4
Q

what is a pharmacophore?

A

drugs that bind to the same target that share a similar structural motif

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5
Q

what is the structural motif used for?

A

it is responsible for binding to the receptor

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6
Q

what do the other parts of the drugs do?

A

they are still affecting drug properties such as agonism, solubility, membrane crossing, etc.

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7
Q

what are the chemical properties of the drugs that can be deduced from the structure?

A
  1. size
  2. ionization
  3. solubility
  4. hydrophobicity
  5. stereochemistry
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8
Q

what are the chemical properties of the drugs that affect their biological activity?

A
  1. membrane permeability
  2. excretion
  3. metabolism
  4. target binding
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9
Q

how are drug properties affected by the change in pH?

A
  1. solubility
  2. extent of absorption (bioavailability)
  3. binding to receptor
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10
Q

what ionizable groups have a pH <7?

A

aryl carboxylic acid, aryl amine, aromatic amine, alkyl carboxylic acid

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11
Q

what ionizable groups have a pH >7?

A

alkyl amines, phenol, guanidine

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12
Q

how do you predict the ionizable form of the drug?

A

through Henderson-hasselbach equation

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13
Q

how do you estimate the degree of ionization using the Henderson-Hasselbach Equation?

A

pH < pKa = protonated
pH > pKa = deprotonated
pH = pKa ; A- = HA = 1

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14
Q

what is the range in pH where a drug will become more soluble in water?

A

” like dissolves like”
- better solubility achieved by changing pH > 7
- polar molecules dissolve better due to H bond and ionic groups

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15
Q

what is the range of efficiency of passive diffusion

A

ionized drugs can’t cross lipid bilayer
- passive diffusion is most efficient when the drug is mostly neutral
- if the drug is mostly ionized it diffuses slowly
– the un-ionized portion is at equilibrium with the ionized drug
– diffusion rate is proportional with the amount of neutral

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16
Q

how do you know where the drug will be absorbed in the digestive tract based on pKa?

A
  • drugs are best @ a pH where it is mostly neutral ( or closest to )
    – jejunum has most of the drugs and has a pH range of 5-7
    – the stomach has mostly acidic drugs and has a pH range of 1-3
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17
Q

what are the different modes of drug permeation into the body?

A
  • intercellular junctions
  • passive diffusion (lipid cell membranes)
  • transporters
  • endocytosis and exocytosis
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18
Q

How can we order a series of drugs according to their efficiency in passive diffusion?

A
  • ionizable groups cannot pass the membrane
  • more lipophilic is better but not too much or too hydrophobic
  • need the pH to be neutral because it will diffuse better
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19
Q

what are the hydrophobic groups in a drug structure?

A

methyl
chloro
phenyl
hexyl
cyclohexyl

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20
Q

what are the hydrophilic groups in a structure?

A

carboxylic acid
alcohol
amine
ketone
amide
ester

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21
Q

What are the H-bond donors and acceptors in a drug structure?

A

Donors
OH
NH
Acceptors
O
N

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22
Q

How can we predict the effect of a structural change in a drug on its solubility in water?

A

Lipinski’s rule of 5
- No more than 5 H-bond donors
- No more than 10 H-bond acceptors
- A molecular mass < 500
- A LogP that doesn’t exceed 5
– Like dissolves like
– More polar and ionizable groups along with H bonds
– Be lipophilic and hydrophilic

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23
Q

Explain how logP values affect the ability of drugs to reach target sites.

A
  • LogP < 0 ; favors water
  • LogP = 0 ; equal
  • LogP > 0 ; favors octanol (organic)
  • Bigger LogP → more lipophilic
    – Typical values from -1 to 4
  • If logP is > 5 than it will result in bad solubility, oral absorption, and increase metabolic turnover and can increase toxicity
  • LogP helps to cross membrane barriers if in range and helps to determine the drug properties and if its effective
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24
Q

Explain why the relationship of drug effectiveness vs. logP is parabolic.

A
  • The optimal logP is the logP value corresponding to the max of the drug activity
  • Lipophilicity improves drug permeation, but too much lipophilicity may hinder membrane crossing
    – Inc. or dec. based off of logPo
25
Q

How do you calculate ClogP of a drug molecule from the pi values of its groups?

A

Sum of all pi values

26
Q

How do you calculate the pi value of a constituent group from logP values of structurally related drugs?

A

Subtract from total to find ClogP

27
Q

How do we estimate logD using logP and pKa at a given pH?

A

LogD = LogP - (pH - pKa)

28
Q

Explain how the electronic effects of substituent groups affect drug ionization, acidity, and basicity. How can we estimate the electronic effects of substituent groups on drug ionization using Hammett’s values?

A
  • we want unshared electron pairs that can be shared during resonance thru overlapping p-orbitals with aromatic systems
  • o bonds are head to head
  • pi bonds are side to side
    –> single bonds are o and double bonds are pi
  • bases need E- to bond with H+
    –> determines if more or less basic
29
Q

Define Hammett’s values

A

determines electronic effects of a functional group
- withdrawing and donating here
- determined by pKa
- same group can have a - value at one position and a + value at another

30
Q

Explain the difference in inductive effect and resonance effect

A

position is critical
- meta is inductive only
- other/ para are both
–> it is done through o bonds and lone pairs that occur through conjugated pi bonds
—-> resonance is through pi bonds and inductive is through both bonds

31
Q

electron-DONATING groups

A

negative value and decrease acidity ( more basic )
- inductive groups
– o bonds
– ex: alkyl groups
- resonance groups
– pi bonds and lone pairs
– ortho/para directing
– ex: OR, SR, OCOR, NH2, NR2, NHCOR

32
Q

Determine the change in acidity or basicity of a drug upon the change in the chemical substituents.

A

look at the values because the position determines if it is inductive or resonance effect
- donating groups increase pKa and is less acidic and more basic
- withdrawing groups decrease pKa and more acidic and less basic

33
Q

Why doe we use F instead of H?

A

F is a isostere of H
– share a similar structure and electronic effects
– values are similar and little effect when using F
- H is metabolically vulnerable and F is metabolically resistant

34
Q

electron- WITHDRAWING groups

A

positive value and inc. acidity (less basic)
- inductive groups
– o bonds
– ex: NO2, CN, COOH, COOR, CHO, X, OR, SR
- resonance groups
– ortho/ para directing
– overlapping p-orbitals with electronegative groups
– ex: NO2, CN, CHO, COOR, SO2R

35
Q

how do you identify chiral centers from drug structures?

A
  • have 4 different substituents on chiral carbon
  • most drugs have chiral carbons and all receptors do
  • Easson-Stedman Hypothesis
    —> more potent enantiomer must be involved in minimum of 3D with receptor
36
Q

Explain the differences between R/S, d/l, D/L nomenclature systems.

A

R/S
-by absolute configuration
- requires 3D arrangement for groups
- primary method for drugs
d/l & +/-
- experimentally determined
- optical rotation
- dependent on solution condition
D/L
- by relative configuration to glyceraldehyde
- obsolete; only for amino acids and sugars
- amino acids in proteins (except Gly) are all L-amino acids; most are S, but Cys is R

37
Q

Determine R/S and E/Z notations for drugs from their structures.

A

R/S
- determine priority of groups
- put lowest away
- determine in counterclockwise or clockwise based on priority rule
E/Z
- cis and trans
- cis is Z and means same side
- trans is E and means opposite sides

38
Q

Explain why drug enantiomers have different biological properties.

A

they have different properties based on the chiral carbons
- Arnold Piutti made the observation
- not superimposable and miror images
- different configurations can lead to many different properties such as optimal rotation

39
Q

Explain how the absolute stereochemistry of a molecule can influence receptor binding.

A

it matters due to interactions with various proteins
– metabolism
– permeation by transporters
– nonspecific binding to serum proteins
- they can have different R/S and same orientation but different properties

40
Q

List factors other than receptor binding that result in different biological properties of drug enantiomers.

A
  • optical rotation
  • metabolism
    – permeation by transporters
    – nonspecific binding to serum proteins
    —-> pharmacology, pharmacokinetics, metabolism, toxicity, immune response
41
Q

Explain the potential issues of racemic mixtures as drugs.

A

most drugs are sold as racemic mixtures because separating them is difficult and costly
–> ibuprofen
- although if the inactive enantiomer has serious side effects, it must be sold as the pure enantiomer instead
–> naproxen; other form leads to liver poisoning (R)

42
Q

When a pair of stereoisomers are given, determine whether they are enantiomers, diastereomers, or geometric isomers.

A

Enantiomers: a pair of stereoisomers non-superimposable mirror images
–> Ex: 1s,2r and 1r,2s
—— changes both chiral carbons
Diasteromers: a pair of stereoisomers that are not mirror images
–> Ex: 1s,2r and 1s,2s
—- only changes 1 chiral carbon
Geometric Isomers: are molecules with double bonds
– E/Z
—- Cis is Z and same
—- trans is E and different

43
Q

Determine the Kd value from a binding isotherm

A

DR/ Rt = D/ kD +D
When D = Kd Dr/rt = ½
- Only 50% of receptors are occupied here
When D &laquo_space;Kd; Dr/rt = 0
When D&raquo_space; Kd ; Dr/rt = 1

44
Q

Calculate delta G from Kd or vice versa.

A

Use the equation
- delta G = -RTlnKd
- R is the gas constant ( 8.314 )
- T is the temp in Kelvin ( 273.15 + C )

45
Q

Estimate the change in Kd from the change in delta G or vice versa.

A

The smaller the Kd, the stronger the binding
- Picomolar is the smallest and millimeter is biggest
Typically when using the equation stated above the change is really a 10 fold for Kd and 1.4 delta G change

46
Q

Explain the characteristics of the type of interactions between drugs and receptors.

A

Hydrophobic interactions
Electrostatic interactions
Hydrogen bonding
Interactions with aromatic rings

47
Q

what are hydrophobic interactions

A

attraction with nonpolar groups in water
- these interactions minimze the area of nonpolar bonding
- most common between protein-ligands
—. weak but abundant
Amino Acids
— aliphatic: Ala, Val, Leu, lle, Met, Pro
— aromatic: Phe, Trp

48
Q

what are the electrostatic interactions

A

charge-charge
– + and - interactions
– operate over long distances
– amino acids
— Cationic: Lys, Arg, His
— Anion: Asp, Glu, Cys
ion-dipole & dipole-dipole
– water is dipole
– dipoles in proteins, backbone amine, and alpha helix

49
Q

what is hydrogen bonding?

A

occurs between 2 electronegative atom
- distance between 2 of them is typically 2.7-3.2
- sensitive to orientation and overlapping orbitals
- ionic h-bonds are stronger than neutral ones

50
Q

what are the different interactions with aromatic rings

A

attractions between electron rich (red) and electron deficient (blue) regions
- pi stacking
– parallel stacking of aromatic rings
– stacking in DNA double helix
- T stacking
– edge to face interaction
- cation-pi interaction
– interaction between a + charge and aromatic ring

51
Q

Explain the concept of QSARs.

A

Quantitative structure-activity relationship
They are mathematical models describing the correlation between drug structures and activities
- Derived from statistical regression
Information of the receptor is not necessary

52
Q

List the structural descriptors used for simple QSAR models.

A

Molecular descriptors
Numerical parameters describing chemical properties that can be directly determined by the drug structure
- Used as variables in QSAR variables
Examples
– Drug as a whole: LogP, LogD, molecular weight, pKa
–Fragments: pi values, sigma values, size

53
Q

Distinguish the use of the training set and the test set in QSAR modeling

A

Training is phase 1
– Determines parameters (P1,P2, etc.) of a mathematical model using a training set
Testing is phase 2
– Checks the validity of the model using a test set
–> Both training set and test set contain drugs with known activity data
–> Only validated, model can be used to predict the activity of the drugs without known activity data

54
Q

Explain different approaches for lead discovery and lead optimization.

A
  • Drug discovery and development process
  • Basic research
  • Target
  • Lead
    – Discovery
    »»Natural products
    »»Antimetabolites
    »»Structure-based drug design
    »»High throughput screen
    »»In silico drug design
    – Optimization
    »»Structure-based drug design
    »»QSAR
    »»Isosteric replacement
    »»prodrug
  • Drug candidate
  • Preclinical and clinical trials
55
Q

Explain the uses of bioisosteres.

A

Functional groups or atoms that have -similar steric and electronic properties and produce similar effects on targets
Uses
–Improve pharmacokinetics
–Improve selectivity
–Simplify the synthesis process
–Reduce side effects
–Avoid patent issues

56
Q

Explain the uses of prodrugs.

A

Inactive or carrier form of a drug that is transformed in vivo to the active drug form
- Uses
– Prolong or shorten the duration of action
– Help localize a drug to a specific target site
– Take advantage of active transport processes
– Solve a formulation problem
– Decrease toxicity or side effects

57
Q

Explain how prodrugs are activated via in vivo.

A

Enzymatically
- Example: remdesivir
—It is a prodrug
—Enzymatically converted to a nucleotide analog, where interferes with viral RNA production

58
Q

How can you propose a structural change to increase affinity when the structure of a drug in the binding pocket is given?

A

Structure based design
We want a snug binding pocket so a water molecule cannot get in
Once we add something and hydrogen bond there is not a gap and then there is better and much tighter binding

Patho 2023 (37 decks)

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