3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular...

25
3D-QSAR

Transcript of 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular...

Page 1: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

3D-QSAR

Page 2: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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 .

Page 3: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

QSAR and Drug Design

QSAR

New compounds with improved biological

activity

Compounds + biological activity

Page 4: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

Pysicochemical properties

Hydrophobicity of the molecule (p)

Hydrophobicity of substituents (π)

Electronic properties of substituents ( )s

Steric properties of substituents (Es)

Page 5: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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

Page 6: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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

Page 7: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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

Page 8: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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

Page 9: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

QSAR and 3D-QSAR SoftwareTripos – CoMFAVolSurfMSI – Catalyst Serius

Page 10: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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

Page 11: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

NHCH3

OH

HO

HO

Active conformation

Build 3Dmodel

Define pharmacophore

Page 12: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

NHCH3

OH

HO

HO

Active conformation

Build 3Dmodel

Define pharmacophore

Page 13: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

3D-QSAR

•Place the pharmacophore into a lattice of grid points

•Each grid point defines a point in space

Grid points

..

.

.

.

Page 14: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

3D-QSAR

•Each grid point defines a point in space

Grid points

..

.

.

.

•Position molecule to match the pharmacophore

Page 15: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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

Page 16: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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

. ..

..

Page 17: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

3D-QSAR CASE STUDY

Anticholinesterase used in the treatment of Alzheimer’s disease

N

NH2

Page 18: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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)

Page 19: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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

Page 20: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

3D-QSAR CASE STUDYPossible Alignment

Overlay

Good overlay but assumes similar binding modes

Page 21: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.
Page 22: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.
Page 23: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

3D-QSAR CASE STUDYPrediction6-Bromo analogue of tacrine predicted to be active (pIC50 = 7.40)Actual pIC50 = 7.18

NBr

NH2

Page 24: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

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)

Page 25: 3D- QSAR. QSAR A QSAR is a mathematical relationship between a biological activity of a molecular system and its physicochemical parameters. QSAR attempts.

Presents by:Azar Imanpoor

Super visor:Dr. Parcheh Baf