Physicochemical Parameters in Drug Design Flashcards
Drug action requires
- absorption of the drug, distribution by body fluids thru membranes, escaping escessive distribution (or durg loss) and penetration at the active site
- the right orientation, shape and conformation in order to interact with receptors
- removal of the drug from the receptor and metabolism to an excretable form
drug action is dependent upon
- physicochemical properties of a drug
- host physiological and biochemical properties (biological action)
which parameters relatng to drug action can be changed
a) physicochemical properties of a drug
b) host physiology and biochem properties
physicochemical
hydrophilic molecules are
- polar, i.e. like water
- generally lipophobic i.e. not lipid soluble, don’t cross membranes
hydrophobic molecules
- non-polar; doesn’t like water
- lipophilic - lipid soluble, crosses membranes
the basis for drug design is
relationship between chemical structure and biological activity
pharmacological activity of drugs is either
- structurally specific
- structurally non-specific
Structurally specific pharmacological activity depends on
- the drugs chemical characteristics such as:
- the structure, shape, and conformation for binding of drug to receptor site
structurally non-specific pharmacological activity depends on
the interaction with cell membranes and is more dependent upon the drug’s physical characteristics than chemical characteristics
what is the receptor site theory
- ability of the drug to bind to the receptor
- lock and key - right configuration
what is the occupational theory of response
the intensity of drug effect is proportional to the number of receptors occupied by the drug
the ability of a drug to bind to the receptor relates to the
chemical structure of the drug
the chemical reactivity of the drug depends on
- bonding ability of drug to receptor
- precision of fit
- shape and conformation of the drug
a pharmacophore is
the functional group of a drug which is involved in binding to the receptor
Agonists have better drug receptor fit than antagonists which results in
increased drug response
True/False The stereochemistry of both receptor site surface and drug are important
True
differ in activity if interaction is at an asymmetrical carbon
enantiomorphs
contain groups that ar spatially and electronically equivalent
Bioisosteres
act as an antagonist to normal metabolites
isosteres
6 mechanisms of drug action
- induction of enzymes e.g. protein synthesis
- inhibition of DNA/RNA synthesis
- interference with protein synthesis
- inhibit enzyme catalyzed reactions
- formation of chelation complexes
- interference with cell membrane permeability
when drugs induce enzyme protein synthesis
- enzyme activity increases
- due to allosteric binding which triggers conformational changes in the enzyme allowing the substrate to bind more effectively
- coenzymes, vitamins & cofactors activate enzymes by complexation and stereochemical interaction
- e.g. barbituates, antihistamines
describe the MoA for drugs which interfere with DNA or RNA synthesis
- include antimetabolites, chelating agents, alkylating agents
- inhibit nucleic acid synthesis
- interefere with DNA replication or RNA protein transcription
the pharmacological effect of a drug depends on
- interactions between the drug molecule and receptor
- i.e. receptor binding
the ability of a drug to produce it effect depends on the complementatrity between
the drug and receptor
Quantitative structure activity relationship relates
biological activity of a drug to its chemical structure
when can QSAR be used
- for lead optimization
what does QSAR describe
the relationship between the chemical structure of the drug and the drug’s activity
as it relates to QSAR the activity of a drug is a function of these 3 effects
- electronic
- steric
- hydrophobic or solvent partitioning effects
electronic effects are determined using the
Hammett equation
what is the hammett equation and explain each term
Pσ = log K/K0
P = proportionality constant or sensitivity of the reaction to the substituents
σ = Hammet constant
K = rate constant subtituent
K0 = rate constant reference product
this equation is a measure of the overall electronic (polar) effect of a substituent on the reaction centre relative to the unsubstituted molecule
the hammet equation
what is this equation, what are the equation parameters, and how can the value of σ be calculated
σx = log Kx/KH
equation for hammett constant
- where σx = the electronic effect of x on the rign
- Kx = dissociation constant of benzoic acid with substituent x
- Kh = dissociation constant of benzoic acid at 25c
- σx = pKa0 - pkax = delta pKa
measure of polarity of substituent group
in the hammet equation as P increases solvent polarity
- decreases
- a large P has greater sensitivity to substituent effects
what did the hammett equation suggest
- that the effects of (m and p) substituents on aromatic rings (benzoic acid) are similar for different reactions that have the same chemical backbone and can be used to predict the electronic effects of substintuenat on the rate constants of a reaction
the polarity of a drug has an impact on (4 things)
- effect of drug
- solubility
- ability to cross membranes
- ability to reach intended site of action prior to being excreted
hammett constants with high values are associated with electron donating or withdrawing groups which increase or decreas the acidity and rate of the reaction
- electron withdrawing
- increase
- low values of hammet constants are associated with electron donating substituent groups and low reaction rate
QSAR is impacted by these 3 things
- influence of remote substituents on reactivity of the backbone of a molecule
- pKa
- orbital energies
True/False: the effects of substituents in many reactions involve ortho and para substitued benzenes
- False
- Meta and para
- are correlated with the acid strengths of benzoic acid
describe whether each of these groups have postive, negative or no electronic effect on σm or σp
- Electron withdrawing groups
- electron donating groups
- hydrogen
- Electron withdrawing groups
- Positive
- electron donating groups
- Negative
- hydrogen
- zero or no electronic effect
True or false:
meta σ contants have both inductive and resonance effect while para σ contants have inductive effect only
False
meta σ contants have only inductive effect while para σ constant have both inductive and resonance
what is through resonance
the effect of resonance interactions between substituent groups and site of action
they facilitate or hinder the transition state
what is the linear free energy relationship
- Taft’s theory
- way to separate polar, steric and resonance effect of the rates of base and acid catalyzed hydrolysis of esters
- measure of the polar effect of substituent in the ortho position
- the reference substance group is methyl group
how is electronic effect measured, or Linear Free Relationship, using Taft’s substituent
σ* = 1/P [log (k/ko)b - log (k/ko)a]
K = rate constant hydrolysis substituted compound
Ko = rate constant hydrolysis methyl derivative
What do the first and second portion of the Taft Linear Free Relationship equation measure
σ* = 1/P [log (k/ko)b - log (k/ko)a]
Basic hydrolysis
acid hydrolysis
in the linear free relationship analysis basic hydrolysis is influenced by which effects (steric, inductive, polar)
- polar only
what is a criticism of the Linear Free Energy analysis by Taft
transition states of acid and basic hydrolysis differs somewhat when the taft substituent constant σ* is > 0 and <0.
- when the taft substituent constant σ* is > 0 then it is a stronger electron withdrawer than the methyl group,
- when the taft substituent constant σ* is < 0 then it is a stronger electron donor than the methyl group
lipophilicity of a drugs is defined by its
partition coefficient
how is partition coefficient calculated, what are each of the terms
- P = Corg/Caq
- C = concentration of drug
- Corg = concentration drug in organic phase
- Caq = concentration drug in aqeous phase
which is the most widely used QSAR parameter
partition coefficient
what does lipohilicity of a drug impact
- drug interactions
- passage across membranes
- absorption, distribution, metabolism and excretion
out of ADME which are dependent upon drug lipophilicity
ADE
if a drug has a high partition coefficient it is hydrophobic or hydrophilic
hydrophobic
if a drug has a low partition coefficient it is hydrophobic or hydrophilic
hydrophilic
what is the system of choice for measuring partition coefficient (P) in QSAR studies, and why
- n-octanol/water due to its simmilarity with biological systems
- water saturated octanol is sufficiently polar that dissolved molecules associate with solvent rather than each other
- it has regular structure that isn’t changed by the presence of solutes
- it is chemically stable, non-volatile and doesn’t absorb UV light
biological membranes are comprise of
hydrophobic alkyl chains and polar groups
who demonstrated that partition coefficients (P) in logarithmic scale are additive
Hansch
How is the Hansch constant (π) calculated
π = Log P(Rx) - Log P(Rh)
where Rx = substituted cmpd
Rh = unsubstituted cmpd
Hansch constants for π fall into 3 categories
- strong electron donating groups (phenols)
- strong electron withdrawing
- those in between (phenoxyacetic acid)
what a some departures from the Hansch π additivity concept (8)
- not applicable to aliphatic compounds
- there is no differentiation between the π CH3 and CH2
- π for H = 0
- does not apply to intermolecular hydrogen bonding
- intramolecular hydrogen bonding
- does not account for steric effects
- does not apply to molecular conformation
- intramolecular hydrophobic bonding
Fragmentation constants is an alternate method to calculate
partition coeffecient
what is the equation to calculate partition coefficients using fragmentation constants
log P = Σin ai fi
where
fi = hydrophobic constant group i
ai = # times the group occurs
how is the hydrophobic fragment constant (f) calculated
fx = πx + fh
what is the additivity concept
all substructures of a drug contribute to biological activity in an additive manner
how does the structure of a molecule influence the activity contribution
e.g. same molecule different conformations
the different conformations have different contribution to activity based upon position
how is the degree of ionization of a drug taken into considtion when determining P?
P = P! (1 - alpha)-1
where
P! = Co/Cw
P! = observed partition coefficient
alpha is degree of ionization
for partially ionized drugs the observed or apparent partition coefficient P! is also known as the
distribution coefficients
in QSAR the effect of substituents on biological property of drugs is the result of changes in
steric, electronic and hydrophobic effects
True/False: electronic, steric and hydrophobic effects are additive
true
linear relationships between activity of a drug and lipophilicity are frequently observed in these processes: name 5 of 7
- binding of drugs by proteins
- drugs exchibiting unspecific toxic effect
- bactericidals
- anesthetics
- narcotics
- fungicidal and
- hemolytic processes
name a drug in which a linear relationship between activity and lipophilicity is observed and what is the impact
- penicillin
- the hydrophobic binding of penicillin to serum protein reduces the potency in vivo by decreasing the concentration present in the system
under equilibrium conditions a drug will partition into different compartments of a biological system according to the relative
lipophilicities
drugs with intermediate lipophilicities appear in
all compartments
highly hydrophilic drugs do or do not readily partition from water through the lipid membrane
Do not
Highly hydrophobic drugs do or do not readily partition into the mebrane?
do
what is the random walk of a drug
- pertains to the slow journey of a drug to the site of action through a series of membranes (related to partition coefficient) and is expresses as [f(P)]
what is the parabolic model for non-linear relationship with biological activity
log (1/C) = a log P + b (logP)2 + C Es + dσ + e
a high log P the molecule is losely or tightly** bound to the lipid phase and **can or cannot cross the aqueous phase
- tightly
- cannot
hansch proposed 2 stages in drug action
- random walk
- attachment to the receptor
the attachement of the drug to the receptor (k) depends on
- the shape of the molecule
- the electron density of the attachment group
- is quantified in terms of electronic and substituent constants
the rate of biological response can be calculated by
- d(response)/dt = A (Kx) C
- where
- A = probability of a molecule reaching the stie of action
- Kx = equilibrium rate constant
- C= applied concentration or dose
- probability of A = f(P)
True/False: substances with low aqueous solubility are able to cross barriers (membranes easily)
False
low solubilty do not cross membranes easily
the parabolic model is the most often sued non-linear model due to its simplicity and general applicability
true/false
true
the bilinear model is used in multiparameter equations to describe the non-linear relationship of these four types of drugs
- enzyme ihnibitors,
- antibacterial,
- antitumor and
- antimalarial drugs
In the absence of resonance interactions, Taft’s steric effect is calculated by where these factors play a prirmary role
Es = Log k/ko
steric
base catalyzed ester reactions show a substantial response to substituent ___________effects
Polar
what is the main application of Es
in systems involving sp2 and sp3 hybridization states e.g. hydrolysis of esters and amines and addition reactions
what are sterimol effects
multiparameter steric interactions not explained by Taft
what is the multiparameter approach to steric interaction involve and what do they explain
- use of van der waals radii
- standard bond angles and lengths
- conformations
- explain spatial arrangements in 5 dimensions
the physicochemical model fo biological activity assumes that the activity of a compound is a function of these three parameters
- steric (Es)
- electronic (σ) and
- hydrophobic (π) (solvent partitioning) effects
partition coefficients are calculated either by
- π constants (hydrophobic/partition)
- or fragementation contants
separate electronic effect constants should be used when
resonance interactions are important
