Computer Aided Molecular Design: A Strategy For Meeting The Challenges We Face

Computer Aided Molecular
Design
A Strategy for Meeting the
Challenges We Face
An Organized Guide
Build Chemical Insight
Discover new molecules
Predict their properties
Working at the Intersection

Structural Biology
Biochemistry
Medicinal Chemistry
Toxicology
Pharmacology
Biophysical Chemistry
Information Technology
Structural Biology
Fastest growing
area of biology
Protein and nucleic
acid structure and
function
How proteins control
living processes
Medicinal Chemistry
Organic Chemistry
Applied to disease
Example: design
new enzyme inhibitor
drugs
doxorubicin
cancer)
(anti-
Pharmacology
Biochemistry of Human Disease
Different from Pharmacy: distribution of

pharmaceuticals, drug delivery systems
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)
Working at the Intersection

Structural Biology
Biochemistry
Medicinal Chemistry
Toxicology
Pharmacology
Biophysical Chemistry
Principles
Structure-Function Relationships
Binding
Step 1: Biochemical Mechanism

Step 2: Understand and control
macromolecular binding
Binding
Binding interactions are

how nature controls
processes in living cells
Enzyme-substrate
binding leads to
catalysis
Protein-nucleic acid
binding controls protein
synthesis
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
Molecular Recognition
Hydrogen bonding
interactions (salt bridges)

Charge-charge
Dipole-dipole
interactions (aromatic)
Hydrophobic (like dissolves like)
Hosts: cyclodextrin
OH
O
HO
O
OH
O
HO
OH
OH
HO
HO
OH
O
HO
HO
HO
HO
OH
HO
HO
O
HO
HO O
HO
O
OH
HO
Hexasulfo-calix[6]arenes
O
O S O
O
S
O
OH
OH
O
OH
OH
OH
OH
O
S
O
O S O
O
O
O
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
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
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
CAMD
Computational techniques to guide
chemical intuition
Design new hosts or guests
Enzyme inhibitors
Clinical analytical reagents
Catalysts
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
Structure Searches
2D Substructure searches
3D Substructure searches
3D Conformationally flexible searches
cfs
2D Substructure Searches
Functional groups
Connectivity
[F,Cl,Br,I]
Halogen substituted
aromatic and a
carboxyl group
O
O
Cl
Query:
Cl
O
Halogen substituted
aromatic and a
carboxyl group
O
N
N
N
N
F
Spatial
Relationships
Define ranges for
distances and
angles
Stored conformation
O(s1)
A
C (u)
O(s1)
3.3 - 4.3
O
6.8 - 7.8
usually lowest energy

3.6 - 4.6
[O,S]
A
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
Cl
3.2
O H
Cl
4.3
O H
Conformationally Flexible
Searches
Cl
3.2
O H
Cl
4.3
O H
Small energy penalty
Steric Energy (kcal/mol)
0
0
60
120
180
240
Dihedral angle
300
360
Angiotensin Converting
Enzyme
Zn containing protease
Converts Angiotensin I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
O
-> Angiotensin II
Cl
Raises blood pressure

Vascular constriction
Restricts flow to kidneys
Diminishing fluid loss
N
N
Losartan
Computer Aided Molecular

Design
Quantitative Structure Activity RelationshipsQSAR
Quantitative Structure Property RelationshipsQSPR
Introduction
Uncover important factors in chemical
reactivity
Based on Hammett Relationships in
Organic Chemistry
Medicinal Chemistry
Guest-Host Chemistry
Environmental Chemistry
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
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
Acetylcholine Esterase
Neurotransmitter
recycling
Design drug that
acts like nicotine

Computer Aided Molecular Design: A Strategy For Meeting The Challenges We Face

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Computer Aided Molecular Design: A Strategy For Meeting The Challenges We Face

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Computer Aided Molecular

Working at the Intersection

Biochemistry of Human Disease

Different from Pharmacy: distribution of

New Ideas From Nature

Working at the Intersection

Step 1: Biochemical Mechanism

Binding interactions are

Understand and control binding ->disease

interactions (salt bridges)

pharmaceutical lead compounds

$830 million to bring a new drug to market

usually lowest energy

Rotate around all

Small energy penalty

Steric Energy (kcal/mol)

Raises blood pressure

Computer Aided Molecular

uses in Pharmaceutical Chemistry

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