Computer Aided Molecular Design

1. Computer Aided Molecular Design A Strategy for Meeting the Challenges We Face

2. An Organized Guide • Build Chemical Insight • Discover new molecules • Predict their properties

3. Working at the Intersection • Structural Biology • Biochemistry • Medicinal Chemistry • Toxicology • Pharmacology • Biophysical Chemistry • Information Technology

4. Structural Biology • Fastest growing area of biology • Protein and nucleic acid structure and function • How proteins control living processes

5. Medicinal Chemistry • Organic Chemistry • Applied to disease • Example: design new enzyme inhibitor drugs • doxorubicin (anti-cancer)

6. Pharmacology • Biochemistry of Human Disease • Different from Pharmacy: distribution of pharmaceuticals, drug delivery systems

7. New Ideas From Nature • Natural Products Chemistry • Chemical Ecology • During the next two decades: the major activity in organismal biology • Examples: penicillin, taxol (anti-cancer)

8. Working at the Intersection • Structural Biology • Biochemistry • Medicinal Chemistry • Toxicology • Pharmacology • Biophysical Chemistry • Information Technology

9. Principles • Structure-Function Relationships • Binding • Step 1: Biochemical Mechanism • Step 2: Understand and control macromolecular binding

10. Binding • Binding interactions are how nature controls processes in living cells • Enzyme-substrate binding leads to catalysis • Protein-nucleic acid binding controls protein synthesis

11. Principles • Structure-Function Relationships • Binding • Understand and control binding ->disease • Molecular Recognition • How do enzymes recognize and bind the proper substrates • Guest-Host Chemistry • Molecular Recognition in Cyclodextrins

12. Molecular Recognition • Hydrogen bonding • Charge-charge interactions (salt bridges) • Dipole-dipole • p – p interactions (aromatic) • Hydrophobic (like dissolves like)

13. Hosts:  cyclodextrin

14. Hexasulfo-calix[6]arenes

15. Molecular Design • Originated in Drug Design • Agricultural, Veterinary, Human Health • Guest - Host Chemistry • Ligands for Inorganic Complexes • Materials Science • Polymer Chemistry • Supramolecular Chemistry • Semi-conductors, nonlinear phenomena

16. Information Technology • Chemical Abstracts Service registered over one million new compounds last year • Expected to increase every year • Need to know the properties of all known compounds: • pharmaceutical lead compounds • environmental behavior

17. Information Technology • Store and Retrieve • Molecular Structures and Properties • Efficient Retrieval Critical Step • Multi-million $ industry • Pharmaceutical Industry • $830 million to bring a new drug to market • Need to find accurate information • Shorten time to market, minimize mistakes

18. CAMD • Computational techniques to guide chemical intuition • Design new hosts or guests • Enzyme inhibitors • Clinical analytical reagents • Catalysts

19. CAMD Steps • Determine Structure of Guest or Host • Build a model of binding site • Search databases for new guests (or hosts) • Dock new guests and binding sites • Predict binding constants or activity • Synthesize guests or hosts

20. Structure Searches • 2D Substructure searches • 3D Substructure searches • 3D Conformationally flexible searches • cfs

21. 2D Substructure Searches • Functional groups • Connectivity • Halogen substituted aromatic and a carboxyl group

22. 2D Substructure Searches • Query: • Halogen substituted aromatic and a carboxyl group

23. 3D Substructure Searches • Spatial Relationships • Define ranges for distances and angles • Stored conformation • usually lowest energy

24. Conformationally Flexible Searches • Rotate around all freely rotatable bonds • Many conformations • Low energy penalty • Get many more hits • Guests adapt to hosts and Hosts adapt to guests

25. Conformationally Flexible Searches • Small energy penalty

26. Angiotensin Converting Enzyme • Zn containing protease • Converts Angiotensin I • Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu • -> Angiotensin II • Raises blood pressure • Vascular constriction • Restricts flow to kidneys • Diminishing fluid loss Losartan

27. Computer Aided Molecular Design Quantitative Structure Activity Relationships- QSAR Quantitative Structure Property Relationships- QSPR

28. Introduction • Uncover important factors in chemical reactivity • Based on Hammett Relationships in Organic Chemistry • Medicinal Chemistry • Guest-Host Chemistry • Environmental Chemistry

29. CAMD • Determine Structure of Guest or Host • Build a model of binding site • Search databases for new guests (or hosts) • Dock new guests and binding sites • Predict binding constants or activity • Synthesize guests or hosts

30. Outline • Hammett Relationships • log P : Octanol-water partition coefficients • uses in Pharmaceutical Chemistry • uses in Environmental Chemistry • uses in Chromatography • Other Descriptors • Multivariate Least Squares • Nicotinic Agonists - Neurobiology

31. Acetylcholine Esterase • Neurotransmitter recycling • Design drug that acts like nicotine

32. Acetylcholine Esterase • RCSB Protein Data Bank (PDB) • Human disease- molecular biology databases • SWISS-PROT • OMIM • GenBank • MEDLINE

33. Acetylcholine Esterase + + Nicotine

34. Hammett Relationships • pKa of benzoic acids • Effect of electron withdrawing and donating groups • based on rG = - RT ln Keq

35. pKa Substituted Benzoic Acids • log Ka - log KaH =  • K aH is the reference compound- unsubstituted

36. Hammett  Constants

37. Sigma-rho plots • One application of QSPR • Activity = rs + constant • Y = mx + b • s: descriptor • r : slope

38. Growth Inhibition for Hamster Ovary Cancer Cells -NH3+ -NO2

39. Octanol-Water Partition Coefficients • P = C(octanol) C(water) • log P like rG = - RT ln Keq • Hydrophobic - hydrophilic character • P increases then more hydrophobic

40. QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles

41. QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles

42. Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles • log(1/C) = 0.869 log P + 1.242 • n = 28 r = 0.965 • subset of alcohols: log(1/C) = 1.49 log P - 0.10 (log P)2 + 0.50 n = 10 r = 0.995

43. log P hydrophobic benzene 2.13 pentanol 0.81 butylamine 0.85 n-propanol -0.23 pyridine 0.64 isopropanol -0.36 diethylamine 0.45 ethanol -.75 methanol -1.27 imidazole -0.08 phenylalanine -1.38 tetraethylammonium iodide -2.82 hydrophillic alanine -2.85

44. Estimating log P • M (aq) –> M (octanol) PG = -RT ln P • M (aq) –> M (g) desolG(aq) • M (octanol) –> M (g) desolG(octanol) • PG = desolG(aq) – desolG(octanol) • PG = Fh2o - Foct • log P = – (1/2.303RT) Fh2o - Foct • 1/2.303RT = – 0.735

45. Solvent-Solute Interaction • desolG(aq) = Fh2o • Free Energy of desolvation in water • desolG(aq) = -RT ln KHenry’s • desolG(octanol) = Foct • Free Energy of desolvation in octanol

46. Descriptors • Molar Volume, Vm • Surface area • Rotatable Bonds, Rotbonds, b_rotN • Atomic Polarizability, Apol • Ease of distortion of electron clouds • sum of Van der Waals A coefficients • Molecular Refractivity, MR • size and polarizability • local non-lipophilic interactions

47. Atomic Polarizability, Apol • Atomic Polarizability • Ease of distortion of electron clouds • sum of Van der Waals A coefficients

48. Molecular Refractivity, MR • Molecular Refractivity, MR • size and polarizability • local non-lipophilic interactions

49. Group Additive Properties, GAPs