1. BL5203 Molecular Recognition & Interaction Section D: Molecular Modeling. Chen Yu Zong Department of Computational Science National University of Singapore Singapore 119260

2. Key Points Computer modeling of molecular recognition. Computer modeling of molecular interaction.

3. Molecular Surface: Conformation change induced by a hinge motion

4. Molecular Surface:

5. Mechanism of Ligand Binding: Molecular surface and substrate binding:

6. Mechanism of Substrate Binding: Molecular surface and substrate binding: DNA-protein complex

7. Computer Modeling of Molecular Surface Molecular surface: a smooth three-dimensional contour about a molecule can be generated by rolling probing spheres on the surface atom represented by a group of spheres of Van der Waals radii.

8. From Surface Profile to Cavity Recognition Estrogen Receptor

9. Representation of a Cavity HIV-1 Protease

10. . Modeling of molecular binding: Ligand-protein docking

11. . Modeling of molecular binding: Ligand-protein docking

12. .

13. .

14. Scoring Functions in Ligand-Protein Docking Potential Energy Description:

15. Scoring Functions in Ligand-Protein Docking Potential Energy Description:

16. Energy Functions in Molecular Mechanics Potential Energy Description: –Torsion (bond rotation) –Hydrogen bonding –van der Waals interactions –Electrostatic interactions –Empirical solvation free energy V =  torsions 1/2 V n [ 1 + cos(n  -  ') ] +  H bonds [ V 0 (1-e -a(r-r0) ) 2 - V 0 ] +  non bonded [ A ij /r ij 12 - B ij /r ij 6 + q i q j /  r r ij ] +  atoms i  i A i

17. Applications of Ligand-Protein Docking in Drug Design Science 1992;257: 1078 Proteins 2001;43:217

18. Example 1: Study of Drug Resistant Mutations by Ligand-Protein Docking Enzyme-inhibitor PDB Id Mutation introduced HIV-1 protease + MK 6391HSGV82A, V82F, V82I, I84V, V82f/I84V, M46I/L63P, V82T/I84V, M46I/L63P/V82T/I84V HIV-1 protease + Saquinavir1HXBV82F, V82I, I84V, G48V, V82F/I84V, V82T/I84V HIV-1 protease + SB 2033861SBGI32V/V47I/I82V HIV-1 protease + VX 4781HPVM46I/L63P, V82T/I84V, M46I/L63P/V82T/I84V HIV-1 protease + U89360e 1GNOV82D, V82N, V82Q, D30F HIV-1 RT + Nevirapine 1VRTL100I, K103N, V106A, E138K, Y181C, Y188H HIV-1 RT + TIBO R82913 1TVRL100I, K103N, V106A, E138K, Y181C, Y188H J. Mol. Graph. Mod. 19, 560-570 (2001).

19. Quality of Modelled Structures Wild type X-ray structure: Blue Modelled mutant: Red Mutant X-ray structure: Green

20. Mutation induced energy change compared with observed drug resistance data J. Bio. Chem.271, 31947 (1996) AIDS 12: 453 (1998) Biochemistry 37, 8735 (1998)

21. Example 2: Prediction of toxicity, side effect, pharmacokinetics and pharmacogenetics by a receptor-based approach Annu. Rev. Pharmacol Toxicol 2000, 40:353-388 1997, 37:269-296 Pharmacological Rev. 2000, 52:207-236

22. Importance of prediction of side effect, toxicity, pharmacokinetics in early stages of drug discovery Most drug candidates fail to reach market Pharmacokinetics (60%), side-effect and toxicity (40%) are the main reason. Large portion of money (USD$350 million) and time (6-12 years) spent on a clinical drug has been wasted on failed drugs. Drug Discov Today 1997; 2:72 Drug Candidates in Different Stages of Development Majority of Candidates Fail to Reach Market Clin Pharmacol Ther. 1991; 50:471

23. INVDOCK Testing on Toxicity Targets CompoundNumber of experimentally confirmed or implicated toxicity targets Number of toxicity targets predicted by INVDOCK Number of toxicity targets missed by INVDOCK Number of toxicity targets without 3D structure or involving covalent bond Number of INVDOCK predicted toxicity targets without experimental finding Aspirin159242 Gentamici n 1752102 Ibuprofen53022 Indinavir64022 Neomycin147166 Penicillin G 76018 Tamoxifen22004 Vitamin C22003 Total683852529 J. Mol. Graph. Mod.J. Mol. Graph. Mod., 20, 199-218 (2001).

24. Toxicity and side effect targets of Aspirin identified from INVDOCK search of protein database PDBProtein Experimental Finding Target Status Toxicity/Side Effect Ref 1a42Carbonic anhydrase IIActivate enzyme activity that may lead to increase in plasma bicarbonate concentration. Implicated Metabolic alkalosis (hypoventilation). Puscas I 1a6aHLA-DR3Change in HLA level Implicated Aspirin-induced asthma Dekker JW 1a7cPlasminogen activator inhibitor Tissue- dependent response of protein. Implicated Hypertension, thrombolysis Smokoviti s A 1d6nHypoxanthine-guanine phosphoribosyltransferase Excess uric acid in serum* 1hdyAlcohol dehydrogenaseInhibition of activity Confirmed Increased blood alcohol level Gentry RT J. Mol. Graph. Mod.J. Mol. Graph. Mod., 20, 199-218 (2001).