Transcript Enzymes - Konkuk

1
Introduction
 Quantitative structure-activity relationships, collectively referred
to as QSARs, are theoretical models that can be used to predict
the physicochemical and biological properties of molecules.
A structure-activity relationship (SAR) is a (qualitative) association
between a chemical substructure and the potential of a chemical
containing the substructure to exhibit a certain biological effect
- similar structures –similar effects
- more potency or improved side effects
A quantitative structure-activity relationship (QSAR) is a
mathematical model that relates a quantitative measure of chemical
structure (e.g. a physicochemical property) to a physical property or to
a biological effect (e.g. a toxicological endpoint)
-similar structures –similar effects but uses parameters to describe the
potency
-parameters – anything (related to drug action) that can be represented
by a numerical values
2
Quantitative Structure-Activity Relationship(QSAR)
QSARs allows the medicinal chemist to some level of prediction by quantifying
physicochemical properties, it should be possible to calculate in advance what the
biological activity of a novel analogue might be.
Two advantages :
- target efforts on analogues and cut down the number of analogues which have to be made.
- if an analogue is discovered which does not fit the equation, it implies that some other feature is
important and provides a lead for further development.
physicochemical features
-refer to any structural, physical, or chemical property of a drug
Graphs and equations-linear regression analysis by the least squares method
A graph –
biological activity ( log 1/C) on the y axis versus
the physicochemical (log P) feature on the x axis
equation of the straight line
y = k1x + k2 where k1 and k2 are constants.
Regression coefficient (r) calculated by computer
-perfect fit, r2 = 1. Good fits generally have r2 values of
0.95 or above
3
Quantitative Structure-Activity Relationship(QSAR)
QSAR – mathematical relationship (equations)
-biological effect vs. physicochemical parameters
Three most studied physicochemical properties
- Hydrophobicity/lipophilicity
- Electronic effects/electron distribution
- Steric Factors
- shape
- size
- Other physicochemical parameters
Biological activity = F {parameters (s)}
4
Quantitative Structure-Activity Relationship(QSAR)
Hydrophobicity /lipophilicity
Hydrophobicity/ lipophilicity
-Crucial to cross cell membranes and may in receptor interactions.
-Changing substituent's -significant effects on hydrophobic character and its biological activity.
Hydrophobic/Lipophilic parameters
Hydrophobic character of a drug – measured experimentally – relative distribution -in
an octanol/water mixture
Relative distribution known as the
partition coefficient (P)
Partition coefficient
log (1/C) = k1 log P +k2
equation shows
-binding of drugs to serum albumin
increases as log P increases.
hydrophobic drugs bind more strongly to serum albumin than hydrophilic drugs
5
Quantitative Structure-Activity Relationship(QSAR)
Partition coefficient – often parabolic
Hydrophobicity/ lipophilicity
log (1/C) = -k1 (log P)2 + k2log P + k3
Negative sign in front of (log P)2 shows P is small, the (log P)2 term is very small and
the equation is dominated by the (log P) term
Hydrophobic/lipophilic parameters
General anaesthetic activity of a range of ethers was found to fit the parabolic equation:
log P of gaseous anaesthetics ether, chloroform, and
halothane are 0.98, 1.97, and 2.3
Hansch – logP ~ 2 hypnotic (CNS drug)
Drugs which are to be targeted for the CNS should have a log P value of approximately 2.
'bright visions’
6
Quantitative Structure-Activity Relationship(QSAR)
Hydrophobicity/ lipophilicity
Lipophilic parameters
- lipophilic substituent constants (π) (or hydrophobic)
contribution of substituents to P
Equation for the hydrophobicity constant (π X) for the substituent (X)PH and Px is the partition coefficient for the standard compound,
and with the substituent
A positive value of π indicates more hydrophobic than hydrogen. A negative value
indicates that the substituent is less hydrophobic.
Example, log P values for benzene (log P = 2.13),
chlorobenzene (logP = 2.84), and benzamide (logP = 0.64)
-benzene is the parent compound, the substituent constants
for Cl and CONH2 are 0.71 and —1.49 respectively.
1.35 is calculated theoretical logP value whereas
1.51 observed for meta chlorobenzamide
7
Quantitative Structure-Activity Relationship(QSAR)
Lipophilic substituent constants (π)
Hydrophobicity/ lipophilicity
π = logPX – logPH
π = logP(C6H5Cl) – logP(C6H6) = 2.84 – 2.13 = 0.71
π = π (substituent 1) + π (substituent 2)…..+ π (substituent n)
-Distribution coefficients (D)
-Ionization
for acids
for bases
log (P/D-1) = pH –pKa
log (P/D-1) = pKa - pH
8
Quantitative Structure-Activity Relationship(QSAR)
Electronic effects/electron distribution
The Hammett constant (σ)
-The electronic effects of various substituents will effect on a drug's
ionization or polarity.
-effect on a drug can pass through cell membranes and strongly bind to a receptor.
-measure of the electron withdrawing (+ σ) or electron donating ability (-σ) of a substituent
-determined by measuring the dissociation of a series of substituted benzoic acids compared
to the dissociation of benzoic acid itself.
σx = log Kx
σ
σ
K
x
x
= log Kx - log K
= pK – pKx
9
Quantitative Structure-Activity Relationship(QSAR)
The Hammett constant (σ)
I = Inductive effects, M= Mesomeric effects/Resonance effects
Insecticidal activity of diethyl phenyl phosphates is example where activity is
related to electronic factors
log (1/C) = 2.282 σ - 0.348
Positive value for (σ) (i.e. electron withdrawing groups) will increase activity , π parameter is
not significant in this drugs. so, do not pass into or through a cell and act against an enzyme
called acetylcholinesterase which is situated on the outside of cell membranes.
10
Quantitative Structure-Activity Relationship(QSAR)
Steric Factors
- shape
- size
Influence the interaction of drug to
enzymes or receptor
The Taft steric parameter (Es)
11
Quantitative Structure-Activity Relationship(QSAR)
Molar refractivity (MR)
n is the index of refraction, M is the molecular
weight, and ρ is the density.
The term M/ρ defines a volume, this is
particularly significant if the substituent has pi
electrons or lone pairs of electrons.
Verloop steric parameter
additive – functional groups
Measuring the steric factor involves a computer programme called STERIMOL which
calculates steric substituent values (Verloop steric parameters) from standard bond
angles, van der Waals radii, bond lengths, and possible conformations for the
substituent.
Other physicochemical parameters
These include dipole moments, hydrogen bonding, conformation, and
interatomic distances. However, difficulties in quantifying these properties
limit the use of these parameters.
12
Quantitative Structure-Activity Relationship(QSAR)
Hansch analysis
-drug activity vs. measurable chemical properties
multi parameter approach
two stages:
- transport to the site of action
- binding to the target site
log 1/C = k1(partition parameter)+k2(electronic parameter)+k3(steric parameter)+k4
log 1/C = k1P - k2P2+k3σ +k4Es+ k5
13
Quantitative Structure-Activity Relationship(QSAR)
Accuracy :
- Greater number of analogs – n=5x ; (x= number of parameters)
- biological data
- the choice of parameters
Use:
- Asses the factors controlling the activity
- predict optimum activity (ideal parameter values)
Sources of parameters
- CRC, CAS, Merck Index, etc.
14