Medicinal Chemistry (EXAM 1) Flashcards
how do you modulate biological activity of the drug?
- binding to the receptor
- moving to the location where the receptor is present
what is a drug?
a drug is any substance that brings a change in biologic function through its chemical actions
how are structure and activity correlated?
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
what is a pharmacophore?
drugs that bind to the same target that share a similar structural motif
what is the structural motif used for?
it is responsible for binding to the receptor
what do the other parts of the drugs do?
they are still affecting drug properties such as agonism, solubility, membrane crossing, etc.
what are the chemical properties of the drugs that can be deduced from the structure?
- size
- ionization
- solubility
- hydrophobicity
- stereochemistry
what are the chemical properties of the drugs that affect their biological activity?
- membrane permeability
- excretion
- metabolism
- target binding
how are drug properties affected by the change in pH?
- solubility
- extent of absorption (bioavailability)
- binding to receptor
what ionizable groups have a pH <7?
aryl carboxylic acid, aryl amine, aromatic amine, alkyl carboxylic acid
what ionizable groups have a pH >7?
alkyl amines, phenol, guanidine
how do you predict the ionizable form of the drug?
through Henderson-hasselbach equation
how do you estimate the degree of ionization using the Henderson-Hasselbach Equation?
pH < pKa = protonated
pH > pKa = deprotonated
pH = pKa ; A- = HA = 1
what is the range in pH where a drug will become more soluble in water?
” like dissolves like”
- better solubility achieved by changing pH > 7
- polar molecules dissolve better due to H bond and ionic groups
what is the range of efficiency of passive diffusion
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
how do you know where the drug will be absorbed in the digestive tract based on pKa?
- 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
what are the different modes of drug permeation into the body?
- intercellular junctions
- passive diffusion (lipid cell membranes)
- transporters
- endocytosis and exocytosis
How can we order a series of drugs according to their efficiency in passive diffusion?
- 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
what are the hydrophobic groups in a drug structure?
methyl
chloro
phenyl
hexyl
cyclohexyl
what are the hydrophilic groups in a structure?
carboxylic acid
alcohol
amine
ketone
amide
ester
What are the H-bond donors and acceptors in a drug structure?
Donors
OH
NH
Acceptors
O
N
How can we predict the effect of a structural change in a drug on its solubility in water?
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
Explain how logP values affect the ability of drugs to reach target sites.
- 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
Explain why the relationship of drug effectiveness vs. logP is parabolic.
- 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
How do you calculate ClogP of a drug molecule from the pi values of its groups?
Sum of all pi values
How do you calculate the pi value of a constituent group from logP values of structurally related drugs?
Subtract from total to find ClogP
How do we estimate logD using logP and pKa at a given pH?
LogD = LogP - (pH - pKa)
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?
- 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
Define Hammett’s values
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
Explain the difference in inductive effect and resonance effect
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
electron-DONATING groups
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
Determine the change in acidity or basicity of a drug upon the change in the chemical substituents.
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
Why doe we use F instead of H?
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
electron- WITHDRAWING groups
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
how do you identify chiral centers from drug structures?
- 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
Explain the differences between R/S, d/l, D/L nomenclature systems.
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
Determine R/S and E/Z notations for drugs from their structures.
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
Explain why drug enantiomers have different biological properties.
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
Explain how the absolute stereochemistry of a molecule can influence receptor binding.
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
List factors other than receptor binding that result in different biological properties of drug enantiomers.
- optical rotation
- metabolism
– permeation by transporters
– nonspecific binding to serum proteins
—-> pharmacology, pharmacokinetics, metabolism, toxicity, immune response
Explain the potential issues of racemic mixtures as drugs.
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)
When a pair of stereoisomers are given, determine whether they are enantiomers, diastereomers, or geometric isomers.
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
Determine the Kd value from a binding isotherm
DR/ Rt = D/ kD +D
When D = Kd Dr/rt = ½
- Only 50% of receptors are occupied here
When D «_space;Kd; Dr/rt = 0
When D»_space; Kd ; Dr/rt = 1
Calculate delta G from Kd or vice versa.
Use the equation
- delta G = -RTlnKd
- R is the gas constant ( 8.314 )
- T is the temp in Kelvin ( 273.15 + C )
Estimate the change in Kd from the change in delta G or vice versa.
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
Explain the characteristics of the type of interactions between drugs and receptors.
Hydrophobic interactions
Electrostatic interactions
Hydrogen bonding
Interactions with aromatic rings
what are hydrophobic interactions
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
what are the electrostatic interactions
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
what is hydrogen bonding?
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
what are the different interactions with aromatic rings
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
Explain the concept of QSARs.
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
List the structural descriptors used for simple QSAR models.
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
Distinguish the use of the training set and the test set in QSAR modeling
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
Explain different approaches for lead discovery and lead optimization.
- 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
Explain the uses of bioisosteres.
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
Explain the uses of prodrugs.
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
Explain how prodrugs are activated via in vivo.
Enzymatically
- Example: remdesivir
—It is a prodrug
—Enzymatically converted to a nucleotide analog, where interferes with viral RNA production
How can you propose a structural change to increase affinity when the structure of a drug in the binding pocket is given?
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
