3D-QSAR
QSARA QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters.
QSAR attempts to find consistent relationship between biological activity and physicochemical properties, so that these “rules” can be used to evaluate the activity of new compounds .
QSAR and Drug Design
QSAR
New compounds with improved biological
activity
Compounds + biological activity
Pysicochemical properties
Hydrophobicity of the molecule (p)
Hydrophobicity of substituents (π)
Electronic properties of substituents ( )s
Steric properties of substituents (Es)
Hansch Equation
•A QSAR equation relating various physicochemical properties to the biological activity of a series of compounds.•Usually includes log P, electronic and steric factors
Log 1C æ
è ö ø= -k (logP)
2 + k
2 logP + k
3 s + k
4 E
s + k
51
Hansch Equation
Log 1C
æ è
ö ø= 1.22 p - 1.59 s + 7.89
Conclusions:•Activity increases if p is +ve (i.e. hydrophobic substituents)•Activity increases if s is negative (i.e. e-donating substituents)
Example:Adrenergic blocking activity of b-halo-b-arylamines
CH CH2 NRR'
XY
Free-Wilson Approach
•The biological activity of the parent structure is measured and compared with the activity of analogues bearing different substituents•An equation is derived relating biological activity to the presence or absence of particular substituents
Activity = k1X1 + k2X2 +.…knXn + Z
•Xn is an indicator variable which is given the value 0 or 1 depending on whether the substituent (n) is present or not•The contribution of each substituent (n) to activity is determined by the value of kn
•Z is a constant representing the overall activity of the structures studied
3D-QSAR
•Physical properties are measured for the molecule as a whole•Properties are calculated using computer software•No experimental constants or measurements are involved•Properties are known as ‘Fields’•Steric field - defines the size and shape of the molecule•Electrostatic field - defines electron rich/poor regions of molecule•Hydrophobic properties are relatively unimportant
Advantages over QSAR•No reliance on experimental values•Can be applied to molecules with unusual substituents•Not restricted to molecules of the same structural class•Predictive capability
QSAR and 3D-QSAR SoftwareTripos – CoMFAVolSurfMSI – Catalyst Serius
Comparative molecular field analysis (CoMFA) is one of the well known 3D-QSAR descriptors which has been used regularly to produce the three dimensional models to indicate the regions that affect biological activity with a change in the chemical substitution. The advantages of CoMFA are the ability to predict the biological activities of the molecules and to represent the relationships betweensteric/electrostatic property and biological activity in the form of contour maps gives key features on not only the ligand-receptor interaction but also the topology of the receptor
NHCH3
OH
HO
HO
Active conformation
Build 3Dmodel
Define pharmacophore
NHCH3
OH
HO
HO
Active conformation
Build 3Dmodel
Define pharmacophore
3D-QSAR
•Place the pharmacophore into a lattice of grid points
•Each grid point defines a point in space
Grid points
..
.
.
.
3D-QSAR
•Each grid point defines a point in space
Grid points
..
.
.
.
•Position molecule to match the pharmacophore
3D-QSAR
•A probe atom is placed at each grid point in turn
•Measure the steric or electrostatic interaction of the probe atom with the molecule at each grid point
..
.
.
.Probe atom
3D-QSAR Method
CompoundBiologicalSteric fields (S) Electrostatic fields (E)activity at grid points (001-998) at grid points (001-098)
S001 S002 S003 S004 S005 etc E001 E002 E003 E004 E005 etc1 5.12 6.83 5.34 6.45 6.1
Tabulate fields for each compound at each grid point
Partial least squares analysis (PLS)
QSAR equation Activity = aS001 + bS002 +……..mS998 + nE001 +…….+yE998 + z
. ..
..
3D-QSAR CASE STUDY
Anticholinesterase used in the treatment of Alzheimer’s disease
N
NH2
3D-QSAR CASE STUDY
ConclusionsLarge groups at position 7 are detrimentalGroups at positions 6 & 7 should be electron-withdrawingNo hydrophobic effect
Conventional QSAR Study 12 analogues were synthesised to relate their activity with the hydrophobic, steric and electronic properties of substituents at positions 6 and 7
N
NH2
R1
R2 6
7 9
C è øLog 1 æ ö= pIC50 = -3.09 MR(R1) + 1.43F(R
1,R
2) + 7.00
Substituents: CH3, Cl, NO2, OCH3, NH2, F (Spread of values with no correlation)
3D-QSAR CASE STUDYCoMFAAnalysis includes tetracyclic anticholinesterase inhibitors (II)
N
NH2
R1
R2
R3
R4
R5II
1
2
3
8
7
•Not possible to include above structures in a conventional QSAR analysis since they are a different structural class•Molecules belonging to different structural classes must be aligned properly according to a shared pharmacophore
3D-QSAR CASE STUDYPossible Alignment
Overlay
Good overlay but assumes similar binding modes
3D-QSAR CASE STUDYPrediction6-Bromo analogue of tacrine predicted to be active (pIC50 = 7.40)Actual pIC50 = 7.18
NBr
NH2
REFERENCESQSAR and 3D QSAR in drug
design Part1:methodology Hugo Kubinyi
QSAR and 3D QSAR in drug design .Part1:application Hugo Kubinyi
3D QSAR study of Potent Inhibitor of Phosphodiesterase-4 Using a CoMFA Approach(zhaoqi yang and pinghua sun)
Presents by:Azar Imanpoor
Super visor:Dr. Parcheh Baf