3D-QSAR

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A brief understanble description of 3D-QSAr

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3D-QSAR:

3D-QSAR Presented by Tanuja Dodda Asst. proffesor M.S Pharmacoinformatics

QSAR:

QSAR

QSAR and Drug Design:

QSAR and Drug Design QSAR New compounds with improved biological activity Compounds + biological activity

Pysicochemical properties:

Pysicochemical properties Hydrophobicity of the molecule (p) Hydrophobicity of substituents ( π ) Electronic properties of substituents ( s) Steric properties of substituents (E s )

PowerPoint Presentation:

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 1 C æ è ö ø = - k (log P ) 2 + k 2 log P + k 3 s + k 4 E s + k 5 1

PowerPoint Presentation:

Hansch Equation Log 1 C 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

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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 = 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 not The 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 studied

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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 Can be applied to molecules with unusual substituents Not restricted to molecules of the same structural class Predictive capability

QSAR and 3D-QSAR Software:

QSAR and 3D-QSAR Software Tripos – CoMFA VolSurf MSI – Catalyst Serius

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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

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Active conformation Build 3D model Define pharmacophore

PowerPoint Presentation:

Active conformation Build 3D model Define pharmacophore

PowerPoint Presentation:

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

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

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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

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3D-QSAR Method Compound Biologica l Steric 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 etc 1 5.1 2 6.8 3 5.3 4 6.4 5 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 . . . . .

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3D-QSAR CASE STUDY Anticholinesterase used in the treatment of Alzheimer’s disease

PowerPoint Presentation:

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 è ø Log 1 æ ö = pIC 50 = - 3.09 MR(R 1 ) + 1.43F(R 1 , R 2 ) + 7.00 Substituents: CH 3 , Cl, NO 2 , OCH 3 , NH 2 , F (Spread of values with no correlation)

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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 class Molecules belonging to different structural classes must be aligned properly according to a shared pharmacophore

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

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

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