QSAR

Introduction Quantitative structure-activity relationships (QSAR) represent an attempt to correlate structural or property descriptors of compounds with activities. These physicochemical descriptors, which include parameters to account for hydrophobicity, topology, electronic properties, and steric effects, are determined empirically or, more recently, by computational methods. Activities used in QSAR include chemical measurements and biological assays. QSAR currently are being applied in many disciplines, with many pertaining to drug design and environmental risk assessment. Need of qsar In analog approach of drug development, analogs of 1. 2. Natural products Synthetic products

Are synthesized to have the similar biological activity. Normally specific functional group or groups of the compound are responsible for biological action , known as the pharmacophore. However to get the desired activity in a given biological system, this pharmacophore needs to be modified by addition of one or more functional groups in a specific geometrical or spatial arrangement. This comprises very important part of hit identification as well as lead optimization. These modifications are done according to the relationship between the chemical structure and therapeutic action of the compound, which is predicted by qsar. Therefore the role of qsar: 1. Determines pharmacophore 2. To obtain drugs with a. increased potency b. more selectivity c. more/less duration of action d. less toxicity e. more stability etc 3. Reduce cost if the lead compound is too costly to procure/purify / manufacture in sufficient amounts.

Goal of QSAR study Development of quantitative methods of determining activities of a series of compounds.

Overview of qsar study methods: The Meyer Overton narcosis theory first predicted that efficacy of general anesthetics depend on their lipid water partition coefficient. Further researches into qsar lead to Hammett equation with predicted the pk values of anesthetics as a function of ring substitution , thus giving good correlation between activity and structure. Then the Hansch equation also considered other factors that may influence the activity like free energy change.electron density , biological transport etc to give a more predictive equation for chemical substitution . A typical qsar eqation looks like :

Some Parameters considered/that can be modulated in QSAR study: 1. 2. 3. 4. 5. 6. 7. Homologus series Molecular fragmentation Additional functional groups Isosteric replacements Stereochemistry Ionization etc

Clinical utility of qsar : 1. Predicted pk values 2. The equations for different substitutions/parameters give different corresponding lines in a plot and by correlation and regression analysis the critical parameters for activity is identified + the suitable compound chosen. 3. When a specific activity depends on specific parameter, hypothesis regarding the drug mechanisms can be made. 4. The equation of best fit gives idea which parameter should be modified affect biological activity to improve efficacy/decrease toxicity etc. Examples For inhaled b agonists in asthma treatment, larger aliphatic substitutions to terminal amine groups confers better b2 selectivity: led to b2 selective bronchodilators like salbutamol: more efficacy, less side effect.

Recent advances: Instead of experimentally derived parameters, various quantitative physiochemical descriptors of a proposed drug molecule are analysed in computers using advanced software that predict drug activity. This is called CADD : computer aided drug design. Eg: descriptor like molecular dipole moment/lowest unoccupied molecular orbital (LUMO) etc are used by techniques like CoMFA (comparative molecular field analysis ) to predict and design future drugs. Already protease inhibitors,newer opioids etc has been and are being developed by these technologies. Also molecular mechanics, quantum mechanics etc are being used by computer programs like GOLD, UCSF DOCK for molecular modeling & designing of hypothetical drugs.