Qsar

QSAR IN CHEMISTRY

1. QSAR By Nehla p Department of Pharmaceutical Chemistry Grace college of pharmacy

2. QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP It is said to be a mathematical relationship in the form of an equation between the biological activity and measurable physiochemical parameters. QSAR attempts to identify and quantify the physicochemical properties of a drug and to see whether any of these property has an effect on the drugs biological activity

3. The parameters used in QSAR is a measure of the potential contribution of its group to a particular property of the parent drug. Activity is expressed as log(1/C). C is the minimum concentration required to cause a defined biological response. Physicochemical property as log p..

4. PARAMETERS ‰ Various parameters used in QSAR studies are 1.Lipophilic parameters : partition coefficient, π- substitution constant. 2.Electronic parameters : Hammet constant, dipole moment. 3.Steric parameters : Taft’s constant, molar refractivity, Verloop steric parameter.

5. LIPOPHILIC PARAMETERS Lipophilicity is partitioning of the compound between an aqueous and non-aqueous phase. Partition coefficient: P=[drug] in octanol/[drug] in water High P High hydrophobicity

6. Linear relationship between Log p and Log 1/C Activity of drugs is often related to P e.g. binding of drugs to serum albumin (straight line - limited range of log P ) Log (1/C) Log P . . . . . . . . . 0.78 3.82 Binding increases as log P increases Binding is greater for hydrophobic drugs Log 1 C æ è ö ø = k1 log P + k2

7. Non –linear relationship between Log P and Log 1/C Example 2 General anaesthetic activity of ethers (parabolic curve - larger range of log P values) Log P o Log P Log (1/C) Optimum value of log P for anaesthetic activity = log P o Log 1 C æ è ö ø = - k1 (log P ) 2 + k2log P + k3

8. π- substituent constant or hydrophobic substituent constants: The π- substituent constant defined by H ansch and co-workers. Measure of how hydrophobic a substituent is,relative to H πx= log Px-log P H Benzene (Log P = 2.13) Chlorobenzene (Log P = 2.84) Benzamide (Log P = 0.64) C l C O N H 2 p Cl = 0.71 p CONH = -1.49 2

9. Positive values imply substituents are more hydrophobic than H Negative values imply substituents are less hydrophobic than H Example : meta -Chlorobenzamide C l C O N H 2 Log P (theory) = log P (benzene) + p Cl + p CONH = 2.13 + 0.71 - 1.49 = 1.35 Log P (observed) = 1.51 2 A QSAR equation may include both P and p . P measures the importance of a molecule’s overall hydrophobicity (relevant to absorption, binding etc.) p identifies specific regions of the molecule which might interact with hydrophobic regions in the binding site

10. ELECTRONIC PARAMETERS Hammett Substituent Constant ( s ) Eg. X = electron withdrawing group (e.g. NO 2 ) Charge is stabilised by X Equilibrium shifts to right K X > K H s X = log K X K H = logK X - logK H Positive value

11. X= electron donating group (e.g. CH 3 ) Charge destabilised Equilibrium shifts to left K X < K H s X = log K X K H = logK X - logK H Negative value

12. s value depends on inductive and resonance effects s value depends on whether the substituent is meta or para ortho values are invalid due to steric factors

13. meta -Substitution EXAMPLES: s p (NO 2 ) = 0.78 s m (NO 2 ) = 0.71 e-withdrawing (inductive effect only) e-withdrawing (inductive + resonance effects) Hammett Substituent Constant ( s ) para -Substitution

14. s m (OH) = 0.12 s p (OH) = -0.37 e-withdrawing (inductive effect only) e-donating by resonance more important than inductive effect Hammett Substituent Constant ( s ) EXAMPLES: meta -Substitution para -Substitution

15. STERIC SUBSTITUTION CONSTANT It is a measure of the bulkiness of the group it represents and it effects on the closeness of contact between the drug and receptor site. It is much harder to quantitate. Taft’s steric factor (Es') Measured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditions E s = log k x - log k o k x represents the rate of hydrolysis of a substituted ester k o represents the rate of hydrolysis of the parent ester

16. Molar refractivity (MR)--measure of the volume occupied by an atom or group--equation includes the MW, density(d), and the index of refraction(n)– MR=(n²-1)MW/(n²+2)d Verloop steric parameter- -computer program uses bond angles, van der Waals radii, bond lengths

17. 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 Start with simple equations and elaborate as more structures are synthesised Typical equation for a wide range of log P is parabolic 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

18. 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

19. 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 Method

20. No need for physicochemical constants or tables Useful for structures with unusual substituents Useful for quantifying the biological effects of molecular features that cannot be quantified or tabulated by the Hansch method Advantages Disadvantages A large number of analogues need to be synthesised to represent each different substituent and each different position of a substituent It is difficult to rationalise why specific substituents are good or bad for activity

21. QSAR Software Tripos – CoMFA , COMSIA VolSurf MSI – Catalyst, Serius Docking Software DOCK – Kuntz Flex – Lengauer LigandFit – MSI Catalyst

22. 22 COMPARITIVE MOLECULAR FIELD ANALYSIS CoMFA involves placing of molecules in a grid and to correlate field properties of the molecules with biological activities. Dick Crammer in 1988 Steps Group of compounds having a common pharmacophore is selected . The 3-dimensional structures of reasonable conformation must be generated from 2-dimensional structures.

23. 23 CoMFA 3.The energy minimized structures are fitted to each other using pharmacophore hypothesis. 4.Molecules are then aligned using active analog approach, distance geometry method

24. 24 PHARMACOPHORE SELECTION PHARMACOPHORE L-LIPOPHILIC SITE D-H- BOND DONOR PD-PROTONATED H- BOND DONOR

25. 25 Identification Of Pharmacophore Active conformation Build 3D model Define pharmacophore

26. 26 CoMFA ALIGNMENT

27. 27 CoMFA Once molecules are aligned, a grid or lattice is established which surrounds the sets of analogues in potential receptor space.

28. 28 Each grid point defines a point in space Place the pharmacophore into a lattice of grid points Each grid point defines a point in space Grid points CoMFA

29. 29 CoMFA Each grid point defines a point in space Grid points Position molecule to match the pharmacophore

30. 30 CoMFA A Probe atom is placed at each grid point. Steric and electrostatic fields are calculated for each molecule in every grid point. Next step in a CoMFA is a partial least square analysis to determine a minimal set of grid points necessary to explain measured biological activities of the compounds. CoMFA results are often presented in a graphical form ;with contours :favorable and unfavorable regions of different fields.

31. 31 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

32. VOLSURF The VolSurf program predicts a variety of ADME properties based on pre-calculated models. The models included are: drug solubility Caco-2 cell absorption blood-brain barrier permeation distribution

33. VOLSURF VolSurf reads or computes molecular fields, translates them to simple molecular descriptors by image processing techniques. These descriptors quantitatively characterize size, shape, polarity, and hydrophobicity of molecules, and the balance between them.

34. VOLSURF hydrophobic (blue) and hydrophilic (red) surface area of diazepam.

35. Catalyst Catalyst develops 3D models (pharmacophores) from a collection of molecules possessing a range of diversity in both structures and activities. Catalyst specifies hypotheses in terms of chemical features that are likely to be important for binding to the active site. Each feature consists of four parts: Chemical function Location and orientation in 3D space Tolerance in location Weight

36. Catalyst CYP3A4 substrates pharmacophore Hydrophobic area, h-bond donor, 2 h-bond acceptors Saquinavir (most active compound) fitted to pharmacophore

37. 3 D QSAR In 3 D QSAR, 3D properties of a molecule are considered as whole rather than considering individual substituents. 3D-QSAR involve the analysis of the quantitative relationship between the biological activity of a set of compounds and their three-dimensional properties using statistical correlation methods. 3 D QSAR revolves around the important features of a molecule, its overall size and shape, and its electronic properties.

38. 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