Qsar parameters by ranjeeth k

qsar parameters in principle of drug discovery

1. Qsar physicochemical parameters,hansch analysis and fee Wilson analysis Submitted to: VIMAL JOHN SAMUEL Department of pharmacology DSU Submitted by: Ranjeeth k 1 ST year M pharm Department of pharmacology DSU 03-05-2020 1

2. contents INTRODUCTION PHYSICOCHEMICAL PARAMETERS HANSCH ANALYSIS FREE WILSON ANALYSIS REFERENCES 03-05-2020 2

3. introduction A QSAR is a mathematical relationship between a biological activity of a molecular system and its geometric and chemical characteristics. QSAR attempts to find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds. QSAR involves the derivation of mathematical formula which relates the biological activities of a group of compounds to their measurable physicochemical parameters. These parameters have major influence on the drug’s activity. 03-05-2020 3

4. Physicochemical paramaeters Various parameters used in QSAR studies are: Hydrophobicity: partition coefficient, π- substitution constant Steric Parameters: Taft’s constant, verloop steric parameter Electronic Parameter: Hammet constant, dipole moment 03-05-2020 4

5. hydropobicity Hydrophobic character of a drug is crucial to how easily it crosses the cell membrane and may also important in receptor interactions. Hydrophobicity of a drug is measured experimentally by testing the drugs relative distribution is known as partition coefficient Partition coefficient : Partition coefficient P usually expressed as logP P= (X)octanol (X)aqueous 03-05-2020 5

6. Contd.. π- substituent constant The π-substituent constant defined by hansch and coworkers by the following equation. Partition coefficient can be calculated by knowing the contribution that various substituent , is known as substituent hydrophobicity constant. π x= log Px-log PH 03-05-2020 6

7. Steric Parameters 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 Bulky substituent may help to orient a drug property for maximum binding and increase activity. Taft’s steric factor (Es) It is measure by the comparing the rate of hydrolysis of substituted aliphatic esters against a standard ester under acidic condition. 03-05-2020 7

8. Contd.. Verloop steric parameter • Calculated by software STERIMOL • Gives dimensions of substituent from the standard bond angle, van der waals radii, bond length. 03-05-2020 8

9. Electronic Parameter The electronic effect of various substituent will clearly have an effect on drug ionization and polarity. • Have an effect on how easily drug can pass through the cell membrane or how strongly it can interact with a binding site. The Hammett constant ( σ) sx = log (Kx/K benzoic) Hammett constant takes into account both resonance and inductive effects; thus, the value depends on whether the substituent is para or meta substituted • - ortho not measured due to steric effects 03-05-2020 9

10. Hansch analysis The biological activity of most drugs is related to a combination of physico -chemical properties. In such cases, simple equations involving only one parameter are relevant only if the other parameters are kept constant. In reality, this is not easy to achieve and equations which relate biological activity to more than one parameter are more common. These equations are known as Hansch equations and they usually relate biological activity to the most commonly used physicochemical properties ( logP , electronic,and a steric factor). 03-05-2020 10

11. Contd.. If the range of hydrophobicity values is limited to a small range then the equation will be linear . log(1/C)= k1 log P + k2 s + k3 Es +k4. If the P values are spread over a large range then the equation will be parabolic for the same reasons. log (1/C) = - k1(log P)2 + k2 log P + k3 s + k4 Es +k5 03-05-2020 11

12. 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 03-05-2020 12

13. Contd.. Example: Adrenergic blocking activity of b-halo-b- arylamines Conclusions: • Activity increases if p is + ve (i.e. hydrophobic substituents) •Activity increases if s is negative (i.e. e-donating substituents) 03-05-2020 13

14. Contd.. Hansch Equation Example : Antimalarial activity of phenanthrene aminocarbinols 03-05-2020 14

15. Contd.. Conclusions: • Activity increases slightly as log P (hydrophobicity) increases (note that the constant is only 0.14) •Parabolic equation implies an optimum log Po value for activity •Activity increases for hydrophobic substituents (esp. ring Y) •Activity increases for e-withdrawing substituents (esp. ring Y) 03-05-2020 15

16. Free-Wilson Approach METHOD • 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 03-05-2020 16

17. Contd … Advantages •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 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 •The effects of different substituents may not be additive (e.g. intramolecular interactions) 03-05-2020 17

18. references Patrick L . Graham “ An introduction to medicinalchemistry ’’ 4th edition by Oxford University, NewYork . http://www.ccl.net/qsar/archives/0207/0029.html QSAR: Hansch Analysis And Related Approaches, By Hugo Kubinyi , VCH Publication. Department of Chemistry, Pomona College, Claremont,California The Physicochemical Approach to Drug Design and Discovery (QSAR) Drug Development Research 1267-309 (1981) Hansch , C.. Leo. A.: Substituent Constants for Correlation Analysis in Chemistry and Biology, New York: Wiley- Interscience , 1979. 03-05-2020 18

19. Thank you 03-05-2020 19