Title 1. QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP.pdf ✅

PHARMD GURU Page 3 A major problem in QSAR studies arise because hydrophobic, electronic and steric effect overlaps and cannot be neatly separated. QSAR PARAMETERS: The QSAR approach uses parameters which have been assigned to the various chemical groups that can be used to modify the structure of the drug. The parameter is a measure of the potential contribution of its group to a particular property of the parent drug. The various parameters used in QSAR studies are: 1. LIPOPHILIC PARAMETERS: Partition coefficient, Chromatographic parameters and π— Substitution constant. 2. POLARIZABILITY PARAMETERS: Molar refractivity, Molar volume, Parachor. 3. ELECTRONIC PARAMETERS: Hammett constant, Field and resonance parameters, parameters derived from spectroscopic data, Charge- transfer constant, Dipole moment, Quantum-chemical parameters. 4. STERIC PARAMETERS: Taft’s steric constant, Vander Waal’s radii 5. MISCELLANEOUS PARAMETERS: Molecular weight, Geometric parameters, Conformational entropies, Connectivity indices, other topological parameters. 1) LIPOPHILIC PARAMETERS: Lipophilicity is defined by the partitioning of a compound between an aqueous and a non-aqueous phase. Two parameters are commonly used to represent lipophilicity, namely the partition coefficient (p) and lipophilic substituent constant (π). The former parameter refers to whole molecule, while the latter is related to substituted groups. PARTITION COEFFICIENT: A drug has to pass through a number of biological membranes in order to reach its site of action. Consequently, organic / aqueous system partition coefficient is the obvious Parameters used to measure the movement of drug through these
PHARMD GURU Page 4 membranes. Partition coefficient is generally given as, P = C org . C aqu . ............................ 3 It is a ratio of concentration of substance in organic and aqueous phase of a two compartment system under equilibrium conditions. For easily ionisable drug, correlation must be made as follows: P = C org . C aqu .(1 –α) ................................. 4 α = degree of ionization  The accuracy of the correlation of drug activity with partition coefficient will depend on the solvent system used as a model for the membrane. Both pure water and buffered solution are used for the aqueous medium.  The n-octanol/water system is frequently chosen, because it appears to be a good mimic of lipid polarity; however more accurate results may be obtained if the organic phase is matched to the area of biological activity being studied.  For example, n-octanol usually gives more consistent result for drugs absorbed in GI tract while less polar solvents such as olive oil give more consistent correlation for drugs crossing the blood-brain barrier.  More polar solvents such as chloroform give more consistent value for buccal absorption. n-octanol/ water system has more advantages over other systems:  It is a suitable model of the lipid constituents of biological membrane due to its long alkyl chain and the polar hydroxyl group.  n-octanol has a low vapor pressure, allowing reproducible measurements  n-octanol is UV transparent over a large range, making the quantitative determination of a compound is relatively easy. The nature of the relationship between P and drug activity depends on the range of P values obtained in the compounds used. If this range is small the result may be expressed as a straight line equation having the general form: log 1/c = K1 log P + K2 ....................... 5