QSAR.pptx

QSAR in medicinal chemistry

1. QSAR

2. INTRODUCTI O N Principles of drug designing Improving the selectivity Increasing the selectivity Reduce side effects Arrangement functional groups and identification of a pharmacophore

3. W H A T IS Q S A R ? is a mathematical relashionship a biol o gi c al activity A QSAR b e t w e en system and its geometric of a mol e c ular and c h em i c al 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.

4. 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. QSAR derived equation take the general form: Biological activity = function (parameters) – Activity is expressed as log(1/c). C is the minimum concentration required to cause a defined biological response

5. Physicochemical Parameters Various parameters used in QSAR studies are: H y d r o p h obic i t y : P arti t i on c o e f f i ci e n t, π - substitution constant S t er ic P a r a m e t e r s : T a f t ’ s c o n s t a n t , Han s ch analysis, V erloop steric parameter Ele c t r o n i c P a r a m e t e r : Ham m e t c o n st a n t, dipole moment

6. HYDROPHOBICITY Hydrophobic character of a drug is crucial to how easily it cross the cell membrane and may also important in receptor interactions. Hydrophobicity of a drug is measured experimentally by testing the drugs relative distribution and is known as partition coefficient

7. Partition coefficient : Partition coefficient P usually expressed as logP It is defined as

8. P is a measure of the relative affinity of a molecule for the lipid and aqueous phase in the absence of ionization. 1 -Oc t anol i s a m o s t f r e qu e n tl y use d lip i d phase in pharmaceutical research

9. LogP for a molecule can be calculated from a sum of fragmental or atom based terms plus various corrections. LogP = Σ fragments + Σ corrections

10. Relationship between LogP and Log1/C

11. π-substituent constant The π-substituent constant defined by hansch and co- workers by the following equation. Partition coefficient can be calculated by knowing the contribution that various substituent , is known as substituent hydrophobicity constant. πx= log Px-log PH A positive π value indicates that the π substituent has a higher hydrophobicity than hydrogen

12. A n e g a t i v e π Substituent has i n d i c a t es th a t hydrophobicity t h e π than value a l o w e r hydrogen and the drug favors the aqueous phase. π identify specific regions of the molecule which might interact with hydrophobic regions in the binding sites.

13. ELECTRONIC EFFECT 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. Department of Pharmaceutical Chemistry

14. 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

15. Molar refractivity

16. 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 Bulky substituent may help to orient a drug property for maximum binding and increase activity.

17. T aft ’ s s t e r i c fa c t o r (Es) It is measure by the comparing the rate of hydrolysis of substituted aliphatic esters against a standard ester under acidic condition

18. HANSCH EQUATION: A Q SA R physicochemical equ a t i o n r el a t i ng properties to the v arious biolo g i c a l activity of a series of compounds. U s ual l y includes log P , el e ct r on i c a n d st eric factors. S t a r t with si m pl e e q u a t i on s an d elab o r a t e as more structures are synthesised. T y pi c al equ a ti o n f o r a wide r a n g e of log P is parabolic.

19. 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 β-halo-β-arylamines

20. CRAIG PLOT The Craig plot, named after Paul N. Craig, is a plot of two substituent parameters used in rational drug design. Two most used forms of a Craig plot are plotting the sigma constants of hydrophobicity plotting th e Ham m ett equati o n versus the steric terms of the Taft equation against hydrophobicity.

21. Adva n tages: This plot shows that there is no overall relationship between π & σ Decision can be made about the influence of the substituent on the biological activity considering positive & negative at a glance. Substituents containing similar σ & π values can be identified. It is useful to predict which substituents have to be used in QSAR studies.

22. PHARMACOPHORE: A pharmacophore was first defined by Paul Ehrlich in 1909 as " A molecular framework that carries (phoros) the essential features responsible for a drug’s (=pharmacon's) biological activity“. In 1977, this definition was updated by Peter Gund to "a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecule's biological activity“. The IUPAC definition of a pharmacophore is "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response".

23. Pharmacophore-based drug design 1. Determine identity of a “lead compound”: Screen natural and synthetic banks of compounds for activity Folk medicine Natural ligand Drug already known Computer-aided drug design Computerized search of structural databases

24. 2. Data collection: Publications; patents; biological activity; NMR and X-ray data; physiochemical properties to determine the effects of structural changes on activity of drug: structure-activity relationships (SARs) 3. Analysis: I ntegrate information about drug (and target) to generate hypothesis about activity. This information will result in the identification of a pharmacophore.

25. THAN K YO U