What is QSAR ??
A mathematical relation ships:
measurable molecular properties
correlates
in terms of an equation
Some biological activity
Steps involved in QSAR
*
*:Virtual Screening, Molecular Docking and QSAR Studies in Drug Discovery and Development Programme, M. Rudrapal, D. Chetia, Published 2020, Journal of Drug Delivery and Therapeutics
Step 2: Molecular Modeling
Forms a model of the real word
dealing with the model not with the real word
It is valid as long as it reproduces the real word
Study molecular
properties
Rationalize, interpret
experimental result
Make prediction for
unstudied systems
Molecular
modeling is a
fast, accurate,
cheap way to
Design new
molecules
Step 3: Molecular Descriptors
Numerical values associated with the structural features of chemical compounds
Geometrical descriptors
Electronic descriptors
principal moments of inertia.
molecular volume.
solvent-accessible surface area.
Molecular Surface area.
dipole moment,
Quadrupole moment,
polarizibility
Molar Refractivity
Descriptors falls in 4 classes
Topological descriptors
Hybrid and 3D Descriptors
Atom and Bond Counts
substructure counts
molecular connectivity Indices
Molecular Symmetry
spatial autocorrelation vectors
pharmacophore fingerprints
Eva Descriptors
Descriptors of Molecular Field
Hydrophobicity
Crucial to how easily drug crosses cell membrane and also in receptor interaction
Relative distribution is known as partition coefficient (p)
≠ substituents on lead compounds
concentration of drug in oil phase
P = cocentration
of drug in aqeous phase
≠ hydrophobicity and ≠ p values
Log (1/C)
A straight line would be obtained with equation: Log (1/c) = k1log p + k2
Increasing hydrophobicity increases the biological activity:
• Cross hydrophobic barriers to reach the target
• Interact with the target
P
Hydrophobicity
Hydrophobicity does not increase biological activity to infinity:
• Drug may become poorly soluble in aqueous phase
• Drug may trap in fat deposit and never reach the site of action
• Suspected to metabolism and elimination.
Curve : changes from straight line to parabolic
Small value
the equation is
dominated by first
part of the reaction
Large value the
equation is dominated
by second part of the
reaction
Hydrophobicity
≠ substituents have ≠ hydrophobicity
Measure theoretically the relative hydrophobicity (∏) for substituents w.r.t. hydrogen
∏X : Hydrophobicity constant for substituent x
PX : Partition coefficient for standard compound with substituent
PH :Partition coefficient for standard compound
Electronic effect
Electronic effect of substituent influences the drug ionization and polarity
how easily a drug passes through a cell membrane
Affects
how strongly it interacts with binding site
For substituents on aromatic rings: Hammett’s substituent constant
Measure of electron withdrawing or donating ability of substituents at meta and para position
measuring dissociation of substituted benzoic acid and comparing to benzoic acid itself
Limitations:
• Only few drugs (aromatic system)
• Ortho position is not considered
Electronic effect
Aliphatic electronic substituent constants:
measuring rates of hydrolysis for a series of ester Methyl ethanoate (parent ester)
Rate of hydrolysis varies with substituent X.
(Depending on the electronic effect at site of action).
Electronic effect is purely inductive and denoted as σ1.
Electron-donating group reduces the rate
(σ1<0)
Electron-withdrawing group increases the rate
(σ1 > 0)
Steric factor
Size and shape of drug influence how easily a drug can approach and interact with binding site
Bulky substituent acts like a shield and hinders interaction
Steric factor 1: Taft’s steric factor (Es)
comparing rates of hydrolysis of substituted aliphatic esters with standard ester under
acidic condition.
Steric factors Es = log kx – log k0
X=H, F < CH3
Faster rate (KX > k0)
KX: rate of hydrolysis of aliphatic ester
bearing substituent X.
K0 : rate of hydrolysis of reference ester
X > CH3
Reduces the rate (KX < k0)
Steric Factor
Steric factors 2: Molar refractivity (MR)
Steric factors 3: Verloop steric parameters
volume occupied by an atom or group of atoms
n = index of refraction
MW = molecular weight
d = density
MR is particularly significant with substituents having π
electrons or lone pair of electrons
Involves computer program called Sterimol
calculates steric substituent values from:
• bond angles
• van der Waals radii
• bond lengths
• possible conformation for substituent.
Hansch equation
Biological activity of most drugs
Is related to
combination of physical properties
(log p, π, σ, or a steric factor)
If hydrophobicity values
limited to small range: linear equation
spread over a large range: parabolic equation
Craig plot
Shows values for 2 different physiochemical properties for various substituents
Validation Step
Validation methods are needed to establish the predictiveness of a model
*
*: Molecular docking and QSAR analysis of a few Gama amino butyric acid aminotransferase inhibitors,usman abdulfatai, adamu azairu, sani uba, Egyptian Journal of Basic and Applied Sciences, Volume 5, Issue 1, March 2018, Pages 41-53
Advantage Vs Limitation
• Modifying the structure of lead
compound to retain or to inforce the
desired pharmacological effect.
• Helps in understanding the interaction
between molecule of many functional
groups with their target.
• False correlation in case of
experimental error.
• If dataset is not large enough QSAR
results cant predict the compound of
best reactivity.