Download Lect 11:Computer aided drug design

SMA5422: Special Topics in
Biotechnology
Lecture 11: Computer aided drug
design: QSAR approach.
Chen Yu Zong
Department of Computational Science
National University of Singapore
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Introduction of methodology.
2D QSAR and Pharmacophore
Strategies for improving drug
design cycle:
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Computer-aided drug design:
• Receptor 3D structure unknown:
• QSAR (Quantitative Structure-Activity
Relationship).
Pharm. Res. 10, 475-486 (1993).
Basic Idea:
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Binding => Activity (Reaction):
• Binding:
• Binding free energy DG
– Intermolecular forces (interactions).
– Hydrophobic effect, solvation.
• Activity:
• Reaction constant Keq

Relationship:
DG = -RT ln Keq
Basic Idea:
Objective:

Derive a function that links biological activity of a group of related
chemical compounds with parameters that describe a structural
feature of these molecule.
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This feature also reflects the property of binding cavity on protein
target.
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The derived function is used as a guide to select best candidate for
drug design.
Illustration:
Log(Biological activity) =
f(structural, physical, chemical parameters)
Example:
Log(Biological activity) =>
Size of a side chain of a compound =>
Size and shape of protein cavity
Illustration:
Log(Biological activity) =>
Size of a side chain of a compound => Size and shape of protein cavity
2D QSAR:
LogA = S cc fchem(xc) + ch fhydr(xh) + ce felec(xe) + cst fst(xs)
Abbreviation
Meaning
mg / L, mol / L (and
similar)
milligram per litre, mole per litre etc.
log P
logarithm of the octanol-water partition
coefficient
log D
distribution coefficient
pi, Pi
Hansch hydrophobic substituent constant
MW, Mol Wt
molecular weight
LUMO, Elumo
energy of the lowest unoccupied molecular
orbital
HOMO, Ehomo
energy of the high occupied molecular
orbital
HofF, Heat Form
heat of formation
Dipole
dipole moment
sigma, sigmaX
Hammett constant (on position X)
I-X
indicator variable for presence of X
RX
indicates substituent at position X
MR
molar refractivity
Construction of Pharmacophore:
Superimposing common molecular interaction field contour
resulted in the identification of the consensus pharmacophore
The Concensus Pharmacophore:
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purple = hydrophobic area
green = electron-deficient aromatic system
red = electronegative heteroatoms
pink = protonated nitrogen
blue = large planar ring system.