3D- QSAR

QSAR A 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 (   Steric properties of substituents (E s )

Hansch Equation Hansch Equation A QSAR equation relating various physicochemical properties to the biological activity of a series of compounds.A QSAR equation relating various physicochemical properties to the biological activity of a series of compounds. Usually includes log P, electronic and steric factorsUsually includes log P, electronic and steric factors Log 1 C      - k (logP) 2 + k 2 logP logP+ k 3  + k 4 E s + k 5 1

Hansch Equation Hansch Equation Log1C        Conclusions: Activity increases if p is +ve (i.e. hydrophobic substituents)Activity increases if p is +ve (i.e. hydrophobic substituents) Activity increases if s is negative (i.e. e-donating substituents)Activity increases if s is negative (i.e. e-donating substituents) Example : Adrenergic blocking activity of  -halo-  -arylamines

Free-Wilson Approach Free-Wilson Approach The biological activity of the parent structure is measured and compared with the activity of analogues bearing different substituentsThe 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 substituentsAn equation is derived relating biological activity to the presence or absence of particular substituents Activity = k 1 X 1 + k 2 X 2 +.…k n X n + Z X n is an indicator variable which is given the value 0 or 1 depending on whether the substituent (n) is present or notX n 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 k nThe contribution of each substituent (n) to activity is determined by the value of k n Z is a constant representing the overall activity of the structures studiedZ is a constant representing the overall activity of the structures studied

3D-QSAR 3D-QSAR Physical properties are measured for the molecule as a wholePhysical properties are measured for the molecule as a whole Properties are calculated using computer softwareProperties are calculated using computer software No experimental constants or measurements are involvedNo experimental constants or measurements are involved Properties are known as ‘Fields’Properties are known as ‘Fields’ Steric field - defines the size and shape of the moleculeSteric field - defines the size and shape of the molecule Electrostatic field - defines electron rich/poor regions of moleculeElectrostatic field - defines electron rich/poor regions of molecule Hydrophobic properties are relatively unimportantHydrophobic properties are relatively unimportant Advantages over QSAR No reliance on experimental valuesNo reliance on experimental values Can be applied to molecules with unusual substituentsCan be applied to molecules with unusual substituents Not restricted to molecules of the same structural classNot restricted to molecules of the same structural class Predictive capabilityPredictive capability

QSAR and 3D-QSAR Software Tripos – CoMFA VolSurf MSI – 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 between steric/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

Active conformation Build 3D model Define pharmacophore

Active conformation Build 3D model Define pharmacophore

3D-QSAR 3D-QSAR Place the pharmacophore into a lattice of grid pointsPlace the pharmacophore into a lattice of grid points Each grid point defines a point in spaceEach grid point defines a point in space Grid points

3D-QSAR 3D-QSAR Each grid point defines a point in spaceEach grid point defines a point in space Grid points..... Position molecule to match the pharmacophorePosition molecule to match the pharmacophore

3D-QSAR 3D-QSAR A probe atom is placed at each grid point in turnA probe atom is placed at each grid point in turn Measure the steric or electrostatic interaction of the probe atomMeasure the steric or electrostatic interaction of the probe atom with the molecule at each grid point..... Probe atom

3D-QSAR 3D-QSAR Method CompoundBiologica l Steric fields (S ) Electrostatic fields (E) activity at grid points ( ) at grid points ( ) S001S002S003S004S005 etcE001E002E003E004E005 etc 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 3D-QSAR CASE STUDY Anticholinesterase used in the treatment of Alzheimer’s disease

3D-QSAR CASE STUDY 3D-QSAR CASE STUDY Conclusions Large groups at position 7 are detrimental Groups at positions 6 & 7 should be electron-withdrawing No 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 C  Log1   pIC pIC 50 = MR(R 1 )+ 1.43F(R 1.43F(R 1,R 2 ) Substituents: CH 3, Cl, NO 2, OCH 3, NH 2, F (Spread of values with no correlation)

3D-QSAR CASE STUDY 3D-QSAR CASE STUDY CoMFA Analysis includes tetracyclic anticholinesterase inhibitors (II) Not possible to include above structures in a conventional QSAR analysis since they are a different structural classNot 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 pharmacophoreMolecules belonging to different structural classes must be aligned properly according to a shared pharmacophore

3D-QSAR CASE STUDY 3D-QSAR CASE STUDY Possible Alignment Overlay Good overlay but assumes similar binding modes

3D-QSAR CASE STUDY 3D-QSAR CASE STUDY Prediction 6-Bromo analogue of tacrine predicted to be active (pIC 50 = 7.40) Actual pIC 50 = 7.18

REFERENCES  QSAR 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