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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 (anti-cancer)
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 Information Technology
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 RecognitionHydrogen bonding
•Charge-charge interactions (salt bridges)•Dipole-dipole –interactions (aromatic)• Hydrophobic (like dissolves like)
H
Hosts: cyclodextrinO
HO
O
OH
OH
O
HO
O
HO
OH
O
HO
OHO
OH
O
HOO HO
OH
O HO
O
HO
HO
O
HO
O
OH
HO
O
HO
OOH
HO
Hexasulfo-calix[6]arenes
O
H
O
H
O
H
O
H
O
H
O
H
S
S
S
S
S
S
O
O
O
O
O
O
O
O
O
O
O
O
O
O
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
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
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
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
» Halogen substituted aromatic and a carboxyl group
[
F
,
C
l
,
B
r
,
I
]
O
O
2D Substructure Searches Query:
» Halogen substituted aromatic and a carboxyl group
N
O
O
Cl
O
O
Cl
N
N
N
O
O
F
F
O
F
O
O
N
I
O
N
3D Substructure Searches Spatial
Relationships Define ranges for
distances and angles
Stored conformation» usually lowest energy
C
(
u
)
O
(
s
1
)
O
(
s
1
)
A
A
[
O
,
S
]
O
3.6 - 4.6 Å
3.3 - 4.3 Å
6.8 - 7.8 Å
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
O
Cl
H
O
Cl
H
3.2Å
4.3Å
Conformationally Flexible Searches
O
Cl
H
O
Cl
H
3.2Å
4.3Å
3603002401801206000
1
2
3
4
5
6
Dihedral angle
Ster
ic E
nerg
y (k
cal/m
ol)
Small energy penalty
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
NN
ClO
N N
N N
Losartan
Computer Aided Molecular Design
Quantitative Structure Activity Relationships- QSAR
Quantitative Structure Property Relationships- QSPR
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