3. QSAR.pptx

Quantitative structure-activity relationship (QSAR) is a computational modeling method for revealing relationships between structural properties of chemical compounds and biological activities

1. Quantitative Structure - Activity Relationships (QSAR)

2. Rationale for QSAR Studies T he in vitro and in vivo activity of a substance depends on some biological parameters, including the intrinsic reactivity of the drug, its solubility in water, its ability to pass the blood-brain barrier , its non- reactivity with non-target molecules that it encounters on its way to the target, and others. QSAR correlates measurable or calculable physical or molecular properties of the drug molecules with these specific biological parameters in terms of an equation. These parameters have major influence on the drug’s activity. QSAR derived equation take the general form: Biological activity = function ( parameters )

3. Functions of QSAR Once a valid QSAR has been determined, it should be possible to predict the biological activity of related drug candidates before they are put through expensive and time-consuming biological testing. Activity is expressed as log(1/C). C is the minimum concentration required to cause a defined biological response, which can be determined by QSAR.

4. Parameters Various parameters used in QSAR studies are Lipophilic parameters: partition coefficient, π- substitution constant Polarizability parameters: molar refractivity, parachor Electronic parameters: Hammet constant, dipole moment. Steric parameters: Taft’s constant. Miscellaneous parameters: molecular weight, geometric parameters.

5. Hansch’s Approach in Evaluating Hydrophobicity The first application of QSAR is attributed to Hansch (1969), who developed an equation that relates biological activity to hydrophobicity of a set of structures. log (1/C) = k 1 log P - k 2 (log P) 2 + k 3 σ + k 4 Here , C = M inimum effective dose Log P = Partition coefficient σ = Hammett substituent constant k x = Constants derived from regression analysis 5

6. Hansch’s Approach in Evaluating Hydrophobicity Log P is a measure of the drug’s hydrophobicity, which was selected as a measure of its ability to pass through cell membranes. The log P (or log P o/w ) value reflects the relative solubility of the drug in octanol (representing the lipid bilayer of a cell membrane) and water (the fluid within the cell and in blood ). Log P = Log K (o/w) = Log ([X] octanol /[X] water ) Log P values may be measured experimentally or, more commonly, calculated. 6

7. Molecular Properties in QSAR Many other molecular properties have been incorporated into QSAR studies; some of these are measurable physical properties, such as : Density pK a I onization energy B oiling point H vaporization H hydration 7 Dipole moment (m ) Refractive index Reduction potential Molecular weight Lipophilicity parameter

8. Molecular Properties in QSAR Other molecular properties (descriptors) that have been incorporated into QSAR studies are calculated properties, such as: O vality  Surface area HOMO energy  LUMO energy P olarizability  Charges on individual atoms M olecular volume  Solvent accessible surface area Van-der-Waals surface area  M aximum (+) and (-) charge M olar refractivity  H ardness H ydration energy  Taft’s steric parameter 8