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 -gtdisease
• 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-calix6arenes
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
• -gt 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 r s 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) gt M (octanol) ?PG -RT ln P
• M (aq) gt M (g) ?desolG(aq)
• M (octanol) gt 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 KHenrys
• ?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