ROLE OF QSAR IN RATIONAL DRUG - PowerPoint Presentation

1. ROLE OF QSAR IN RATIONAL DRUG DESIGN (part 2)Mr. A. Rajendiran (Sr. Lecturer)Uni. Inst. of Pharmacy,C.S.J.M. University, Kanpur-24

2. QSAR MODELS:LINEAR FREE ENERGY METHODS (LFE): Two important models included in LFE. 1). HANSCH MODEL 2).FREE WILSON MODEL Hansch analysis attempt to mathematically relate drug activity to measurable chemical properties. It is based on the drug action could be divided into two stages a). Drug transport to its site of action. b). Drug binding to the target site The Hansch equation, General formula: log 1/c= k1 (partition co-eff)+ k2(eletronic parameters)+k3 (steric parameters)+k4 C is the minimum concentration required for biological activity, k1,k2,k3 and k4 are numerical constants obtained by feeding the value of the parameters. 2

3. Modern QSAR Hansch et. Al. (1963)Activity a ‘travel through body’ a partitioning between varied solventsC (Minimum dosage required) p (Hydrophobicity) s (Electronic)Es (Steric) Accuracy of equation will depend on: Number of analogues (n) , accuracy of biological data and the choice of parameters used.

4. Advantages: Hansch equations may be used to predict the activity of an as yet un synthesized analogue.Accuracy may be assessed by standard deviation (s) and the regression constant (r) weakness: Parameter values must be available in the data set. Large number of compounds must be included in the analysis. Expertise in statistics & computer use is essential. Small molecular interaction are imperfect model for biological system. Extrapolation frequently leads to false prediction.4

5. Free Wilson Method:-This method is based on the assumption that the introduction of particular substituent at a particular position always leads to a quantitatively similar effect on biological potency of the whole moleculeBiological activity described by the additive properties of the substituent on a basic structure .Log BR= ∑(Substituent Contribution) + Contribution from the base Molecule.BA = ∑ ai Xi + µWhere BA is the magnitude of the biological activity, Xi is the i th substituent with a value of 1 if present and 0 if not, ai is the contribution of the i th substituent to the BA, and µ is the overall average activity of the parent skeleton. 5

6. Advantages/Limitation:The greater the complexity of the structure, the larger is the number of possible substituent at desired position. Hence the efficiency is high.At each position, the contribution of each substituent can clearly be identified.It is simple , fast and cheap where no substituent constants like pi, sigma, and Es were used.Lack of accuracy as a prediction of activity increments outside the substituent used in the data set by extrapolation is rather impossible. 6

7. 7Reason to use QSAR:Time for experimentInnovation Occurance of enough lab./ Resourcs Cost Prioritization needs Animals ( Save animals), in Silico Model used. Pro active approach for safe chemicals.

8. 8QSAR Softwere Tools available :Sybyl ( Tripos Inc) Insight II Pole bio. Informatique Lyonnais ADMET Predictor- DEREK ( Derek for Window) (Dfw)- CAESAR-

9. 9References: Foye wo. Principles of medicinal chemistry, 5th ed. Philedelphia, Lippincot Williams &wilkins, 2008, 55,77,89 Gennaro, Alfanse, R., Remington The science and practice of pharmacy,20th edition, volume1, Lippincot Williams & Wilkins, reprint 2001, 458-468 Korolkovas A ,Burckhalter JH. Essential of medicinal chemistry. 2nd ed. New Yark; Wily Intersciences, reprint 2008, 140-185 Burger medicinal chemistry and drug discovery, 5th ed, 1995, volume 1, New Yark; Wily Interscience, 497