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QSAR

QSAR (Quantitative Structure Activity Relationship) is a computational method that correlates chemical structures or properties of compounds to their biological activity. It transforms chemical structures into numerical descriptors for properties like solubility or log P (partition coefficient). QSAR models then use these descriptors in mathematical formulas to quantitatively predict biological activity based on structural or physicochemical properties. Key parameters used in QSAR include log P (measure of lipophilicity), Hammett constants (measure electron donating/withdrawing ability), and Taft steric parameters (measure steric effects on size and shape). Hansch analysis and linear free energy models are commonly used methods to perform regression analysis of biological activity data and generate predictive QSAR models.

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QSAR (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP) BY KENCHA SWATHI ASSISTANT PROFESSOR DEPT OF PHARMACEUTICAL CHEMISTRY ADITYA BIPER BANGALORE
QSAR QSAR is a method developed by “Corwen Hansch” It is used to quantify the relationship between the chemical structure of a drug and its biological activity. QSAR = chemical structure of a Drug x biological activity.
DEFINITION • QSAR can be defined as a computerized statistical which gives relevant information regarding the drug to analyse its biological activity for drug design.
• QSAR transforms the chemical structures of a drug or compound ,to set a numerical parameters or descriptors. Various parameters are • Physicochemical parameters- solubility, log P ,protein binding, partition coefficient etc.., • The physicochemical properties are relevant to the biological activity. • QSAR also applies mathematically derived formulas which correlate the physicochemical parameters and the biological activity of a drug or compound. QSAR = f(physicochemical properties) x (biological activity)
• QSAR was further assisted by “Louis Hammett”. • He gave correlation between the electronic properties of organic compound ‘a’ & ‘b’ with its reactivity and equilibrium constant. Biological activity = f(C) C = Physicochemical properties and structural descriptors of a drug • QSAR is not the final answer to drug discovery but one of the refined tool for drug development.
APPLICATIONS OR OBJECTIVES OF QSAR • Prediction of Biological activity-with regression analysis or parameters or their nature and position of substitution . • QSAR gives positive influence on the compound to be guessed. • Understanding the mechanism of action of a drug. • Optimisation of biological activity. • Lead compound search by CADD
• Refinement of synthetic targets. • Economise the new drug development. • Reduction of usuage of animals. • Minimise random synthesis. • Introduction to drug design
LIMITATIONS OF QSAR • It fails to interpret drug-receptor interaction in biochemical terms. • It fails to quantitatively described effects of substituents on non-covalent intramolecular interactions.
QSAR PARAMETERS Partition coefficient Hammet’s electronic parameter Tafts steric parameter Hansch analysis
PARTITION COEFFICIENT • In a pharmaceutical sciences, partition coefficient is the ration of concentration of a compound in the two phases of a mixture of two immisible liquids at equilibrium. • The Partition coefficient is a ratio of concentrations of unionized drug or compound between the two liquid phases. • The logarithm of the ratio of concentrations of the unionized solute in the solvents is called log P.. • One of the solvent is water and the other one is non polar solvent. • Log P value is also known as a measure of lipophilicity.
• For example in octanol-water system is log P oct/wat = log [solute] unionized [solute] unionised log P = log {organic phase} log {acqueous phase} log P = log octanol water Unionised compound octanol water
• Log P is the ideal formula which gives reproducible values on drug absorption. • If log P value is 0 to 1 shows good biological activity. • -ve value or 1.2 ,1.5 = no biological activity. • It is a dimensionless parameter. • Higher the p value value means ,more the lipophilicity ,more absorption,more pharmacological activity of the drug. Log p =lipophilicity+absorption = pharmacological activity of drug • P value varies with the type of solvent. • Log P values are reliable index of solubility ,therapeutic activity.
HAMMETS ELECTRONIC PARAMETER • Distribution of electrons in a drug molecule considerably influences the pharmacokinetic(ADME) & pharmacodynamic activity of the drug. • The unionized form of polar &non-polar drugs are transported across the lipoidal membrane against their ionized counter parts. • When drug reaches to the target site ,the distributed electrons controls the type of the bond. This bond will form with the target site. • The bond between target site and the drug molecule shows drug-receptor interaction and its biological activity.
• Hammett substitution constant is a measure of Electron withdrawing group or electron donating group ability of a drug molecule or its substituent. • σ value is determined by comparing the dissociation constant of substituted drug with that of unsubstituted drug. • When electron withdrawing group is attached to the benzoic acid aromatic ring .It will increase the acidic strength of –COOH. • +ve σ value = substituent is Electron withdrawing group. • -ve σ value = substituent is Electron donating group.
• Therefore σ value for hydrogen is zero. σ = Equilibrium constant for compound Equilibrium constant for monosubstituted compound • Hammett constant takes into account both resonance & inductive effect. • σ value depends on meta or para position. • Hammett constant gives idea about polarizing capacity,ionization,dipole moment,field effect,energy of molecular orbit,atomic net energy etc..,
TAFTS STERIC PARAMETER • The interaction of drug with its receptor is markedly influenced by steric factor of a drug. • The bulk nature of drug,size and shape of the drug influences its binding capacity with an enzyme or receptors. • This effect is reflected for the onset of action or duration of action. • Tafts steric substitution constant ∑ₛ is used for studying the macro molecular steric effects particularly in reactions wherein substituent is near to its reaction centre. • Steric parameter uses a computer programme to calculate the steric substituent values like vanderwals radius, bond length and bond angles etc.., • Tafts steric parameter influences the biological activity of a drug.
DATA ANALYSIS • The data of biological activity & the values of descriptors or parameters generated by the softwares should be analysed regressively to get a meaningful QSAR model (lead model). • QSAR model is considered as a LEAD model to enter into the preclinical and clinical trials. • Cluster analysis and principle component analysis are used to know the better pharmacological activity.
HANSCH ANALYSIS • Generation of a lead model is a platform used to perform the regression analysis. • The most frequently used model is ‘HANSCH’ model . • Hansch model is also called as “LINEAR FREE ENERGY REACTION”model. log (1/c) = a log p + b C = molar concentration of the product a & b = constant values • Alternative model for analysis is “Free Wilson Approach” model.
• The above two methods are used to establish the productiveness of the drug molecule. Example: Triazines (6 membered ring containing 3 Nitrogen atoms) 1. Research is going on triazines for anti-cancer activity. 2. Formula log(1/c) = a log p +b 3. If σ value is decreasing and P value is increasing – Lipophilicity and toxicity increases. 4. If σ value is increasing and P value is decreasing –Lipophilicity and toxicity decreases. 5.Biological activity is normally expressed in log value and is obtained from invitro experiment using software. 6.Determine the LD₅₀ and ED₅₀ .
REFERENCES: • Wilson and Gisvold’s textbook of pharmaceutical and medicinal chemistry. • Textbook of medicinal chemistry by Graham Patrick. • Textbook of Medicinal chemistry by Ashutosh Kar. • A textbook of medicinal chemistry by Ilango.
QSAR
QSAR