QSAR

QSAR

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  Prepared By : MAHENDRAG S M-Pharm,Pharmaceutical Chemistry JSSCP, MYSURU
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  Why QSAR? The numberof compounds required for synthesis in order to place 10 different groups in 4 positions of benzene ring is 104 Solution: synthesize a small number of compounds and from their Physicochemical and Biological activity data derive rules to predict the biological activity of other compounds.
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  What is QSAR? Aquantitative structure-activity relationship (QSAR) is a mathematical relationship which correlates measurable or calculable molecular properties to some specific biological activity in terms of an equation 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. • Understanding QSAR regarding electronic effects, steric effects and lipophilicity.
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  QSAR and DrugDesign •To modify the chemical structure of the lead compound to retain or to reinforce the desirable pharmacologic effect while minimizing unwanted pharmacological and physical and chemical properties, which may result in a superior therapeutic agent; •To use target analogs as pharmacological probes to gain better insight into the pharmacology of the lead molecule and perhaps to reveal new knowledge of basic biology.
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  History  1900, H.H. Meyer and C. E. Overton: lipoid theory of narcosis  1930‘s, L. Hammett: electronic sigma constants  1964, C. Hansch and T. Fujita: QSAR  1984, P. Andrews: affinity contributions of functional groups  1985, P. Goodford: GRID (hot spots at protein surface)  1988, R. Cramer: 3D QSAR  1992, H.-J. Böhm: LUDI interaction sites, docking, scoring  1997, C. Lipinski: bioavailability rule of five  1998, Ajay, W. P. Walters and M. A. Murcko; J. Sadowski and H. Kubinyi: drug-like character Hugo Kubinyi,
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  Different models inQSAR 1.Free Energy Relationships Hansch method : Linear Free Energy Relationships (physicochemical properties) Martin & Kubinyi : Non Linear Free Energy Relationships (physicochemical properties) Free Wilson mathematical model (structural elements) 2.Molecular Modeling 3.Quantum Mechanical Model 4.Topological Method 5.Pattern Recognization
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  Linear Free EnergyRelationships  Linear Free Energy Relationships allow a correlation of substituents with a reaction rate, biological activity, pKa, etc.  To help us understand the magnitude of the sensitivity of parameter to changing substituents, with respect to a reference reaction. what Hammett accomplished • To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula
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  To relate thebiological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula Most common properties studied
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  Lipophilicity and dissociation/ ionization are responsible for transport and distribution of drugs in biological systems. The geometric fit and the complementarity of the surface 3D properties of a ligand are responsible for its affinity to a binding site.
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  Hansch’s Approach • Thefirst application of QSAR is attributed to Hansch (1969), who developed an equation that related biological activity to certain electronic characteristics and the hydrophobicity of a set of structures
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  Log P Log Pis a measure of the drug’s hydrophobicity, which was selected as a measure of its ability to pass through cell membranes. The log P 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) Effect of varying log P & its affects the biological activity. Biological activity normally expressed as 1/C, where C = conc. drug required to achieve a defined level of biological activity. The more active drugs require lower concentration. Partition Coefficient P = [Drug in octanol] [Drug in water] High P High hydrophobicity
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  Example General anaestheticactivity of ethers (parabolic curve - larger range of log P values) Optimum value of log P for anaesthetic activity = log Po Log 1 C     = - 0.22(logP) 2 + 1.04 logP + 2.16 Hydrophobicity of the Molecule Log P o Log P Log (1/C)
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  Hydrophobicity of Substituents -the substituent hydrophobicity constant (p) Notes: •A measure of a substituent’s hydrophobicity relative to hydrogen •Tabulated values exist for aliphatic and aromatic substituents •Measured experimentally by comparison of log P values with log P of parent structure Example: •Positive values imply substituents are more hydrophobic than H •Negative values imply substituents are less hydrophobic than H Benzene (Log P = 2.13) Chlorobenzene (Log P = 2.84) Benzamide (Log P = 0.64) Cl CONH2 pCl = 0.71 pCONH = -1.492
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  Notes: •The value ofp is only valid for parent structures •It is possible to calculate log P using p values •A QSAR equation may include both P and p. •P measures the importance of a molecule’s overall hydrophobicity (relevant to absorption, binding etc) • p identifies specific regions of the molecule which might interact with hydrophobic regions in the binding site Hydrophobicity of Substituents - the substituent hydrophobicity constant (p) Example: meta-Chlorobenzamide Cl CONH2 Log P(theory) = log P(benzene) + pCl + pCONH = 2.13 + 0.71 - 1.49 = 1.35 Log P (observed) = 1.51 2
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  Electronic Effects: The HammettConstant s Hammett constant (1940) s Measure e-withdrawing or e-donating effects (compared to benzoic acid & how affected its ionization) The Hammett substituent constant (s ) reflects the drug molecule’s intrinsic reactivity, related to electronic factors caused by aryl substituents
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  Electronic Effects Hammett SubstituentConstant (s) Notes: •The constant (s) is a measure of the e-withdrawing or e-donating influence of substituents •It can be measured experimentally and tabulated (e.g. s for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid) X=H K H = Dissociation constant = [PhCO 2 - ] [PhCO 2H] +CO2H CO2 H X X
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  + X = electron withdrawing group X CO2CO2H X H X=electron withdrawing group (e.g. NO2) s X = log K X K H = logK X - logK H Charge is stabilised by X Equilibrium shifts to right KX > KH Positive value Hammett Substituent Constant (s)
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  X= electron donatinggroup (e.g. CH3) s X = log K X K H = logK X - logK H Charge destabilised Equilibrium shifts to left KX < KH Negative value Hammett Substituent Constant (s) + X = electron withdrawing group X CO2CO2H X H
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  Steric Factors Taft’s StericFactor (Es) •Measured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditions Es = log kx - log ko kx represents the rate of hydrolysis of a substituted ester ko represents the rate of hydrolysis of the parent ester •Limited to substituents which interact sterically with the tetrahedral transition state for the reaction •Cannot be used for substituents which interact with the transition state by resonance or hydrogen bonding •May undervalue the steric effect of groups in an intermolecular process (i.e. a drug binding to a receptor)
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  Aliphatic electronic substituents •Definedby sI •Purely inductive effects •Obtained experimentally by measuring the rates of hydrolyses of aliphatic esters •Hydrolysis rates measured under basic and acidic conditions X= electron donating Rate sI = -ve X= electron withdrawing Rate sI = +ve Basic conditions: Rate affected by steric + electronic factors Gives sI after correction for steric effect Acidic conditions: Rate affected by steric factors only + Hydrolysis HOMe CH2 OMe C O X CH2 OH C O X
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  Steric Factors Molar Refractivity(MR) - a measure of a substituent’s volume MR = (n 2 -1) (n 2 - 2) x mol. wt. density Correction factor for polarisation (n=index of refraction) Defines volume
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  Thank you