1. SMA5422: Special Topics in Biotechnology Lecture 11: Computer aided drug design: QSAR approach. SMA5422: Special Topics in Biotechnology Lecture 11: Computer aided drug design: QSAR approach. Chen Yu Zong Department of Computational Science National University of Singapore w Introduction of methodology. w 2D QSAR and Pharmacophore

2. Strategies for improving drug design cycle: w Computer-aided drug design: Receptor 3D structure unknown: QSAR (Quantitative Structure-Activity Relationship). Pharm. Res. 10, 475-486 (1993).

3. Basic Idea: w Binding => Activity (Reaction): Binding: Binding free energy  G –Intermolecular forces (interactions). –Hydrophobic effect, solvation. Activity: Reaction constant K eq w Relationship:  G = -RT ln K eq

4. Basic Idea: Objective: w Derive a function that links biological activity of a group of related chemical compounds with parameters that describe a structural feature of these molecule. w This feature also reflects the property of binding cavity on protein target. w The derived function is used as a guide to select best candidate for drug design.

5. Illustration: Log(Biological activity) = f(structural, physical, chemical parameters) Example: Log(Biological activity) => Size of a side chain of a compound => Size and shape of protein cavity

6. Illustration: Log(Biological activity) => Size of a side chain of a compound => Size and shape of protein cavity

7. 2D QSAR: LogA =  c c f chem (x c ) + c h f hydr (x h ) + c e f elec (x e ) + c st f st (x s ) AbbreviationMeaning mg / L, mol / L (and similar) milligram per litre, mole per litre etc. log Plogarithm of the octanol-water partition coefficient log Ddistribution coefficient pi, PiHansch hydrophobic substituent constant MW, Mol Wtmolecular weight LUMO, Elumoenergy of the lowest unoccupied molecular orbital HOMO, Ehomoenergy of the high occupied molecular orbital HofF, Heat Formheat of formation Dipoledipole moment sigma, sigmaXHammett constant (on position X) I-Xindicator variable for presence of X RXindicates substituent at position X MRmolar refractivity

8. Construction of Pharmacophore: Superimposing common molecular interaction field contour resulted in the identification of the consensus pharmacophore The Concensus Pharmacophore: w purple = hydrophobic area w green = electron-deficient aromatic system w red = electronegative heteroatoms w pink = protonated nitrogen w blue = large planar ring system.