computer aided molecular design and information
TRANSCRIPT
Computer Aided Molecular Design
A Strategy for Meeting the Challenges We Face
Rico Del Sesto, Liz Corbeil, Carolyn Mordas, Will Polkinghorn
Challenges
Bacterial Drug ResistanceNew Diseases (AIDS, HONTA, E. Coli)Agricultural Pest ControlEnvironmentally Benign SynthesisEnergy Efficiency (new catalysts)
An Organized Guide
Build Chemical InsightDiscover new moleculesPredict their properties
CAMD
Disciplines InvolvedNatural Products ChemistryStructure-FunctionComputer Aided Molecular DesignInformation Rich Curriculum
Working at the Intersection
Structural BiologyBiochemistryMedicinal ChemistryToxicologyPharmacologyBiophysical ChemistryNatural Products ChemistryChemical EcologyInformation Technology
Structural Biology
Fastest growing area of biology
Protein and nucleic acid structure and function
How proteins control living processes
Medicinal Chemistry
Organic ChemistryApplied to diseaseExample: 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 EcologyDuring the next two
decades: the major activity in organismal biology
Examples: penicillin, taxol (anti-cancer)
Structure Query
O
Rn
Rn
Bell’s Organic Data Base
O
<2.2 - 2.4>
<1.6 - 2.0>
<1.6 - 2.0>
<2.2 - 2.4>
<1.6 - 2.0>
<1.01>
3-METHYCYCLOHEXANONE
1488
C
7
H
1
2
O
m.p. 999
b.p. 163
nd201.4450
d 0.91
irrefF1-433C
nmrrefA1-395B
uvref uv solvent 0
uv freq/absorptivity
0
0
0
0.0
0.0
0.0
Wt 112.17
mass spec peaks112
55
56
69
msref 8PI
propref A2
Spectroscopic Properties Data Bases
Harold M. Bell , Virginia Polytech.5,000 compounds ( ISIS, WWW)
CRC Properties of Organic Compounds28,000 (Windows)
NIST WebBook Gas Phase IR, MS(WWW)
Aldrich, other commercial databases
Working at the IntersectionStructural BiologyBiochemistryMedicinal ChemistryToxicologyPharmacologyBiophysical ChemistryNatural Products ChemistryChemical EcologyInformation Technology
Principles
Structure-Function RelationshipsBinding
Step 1: Biochemical MechanismStep 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 RelationshipsBinding
Understand and control binding ->diseaseMolecular Recognition
How do enzymes recognize and bind the proper substrates
Guest-Host ChemistryMolecular Recognition in Cyclodextrins
Hosts: β− cyclodextrin
O
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 DesignAgricultural, Veterinary, Human HealthGuest - Host ChemistryLigands for Inorganic ComplexesMaterials Science
Polymer ChemistrySupramolecular ChemistrySemi-conductors, nonlinear phenomena
CAMD
Computational techniques to guide chemical intuition
Design new hosts or guestsEnzyme inhibitorsClinical analytical reagentsCatalysts
Information Technology
Chemical Abstracts Service registered over one million new compounds last year
Expected to increase every yearNeed to know the properties of all known
compounds:pharmaceutical lead compoundsenvironmental behavior
Information Technology
Store and Retrieve Molecular Structures and PropertiesEfficient Retrieval Critical StepMulti-million $ industryPharmaceutical Industry
$3-$5 million to bring a new drug to marketNeed to find accurate informationShorten time to market, minimize mistakes
High Throughput Screening
Test 10,000-100,000’s of compoundsRobotics
IndividuallyPfizer: 250,000 libraryCompact shelving
Combinatorial ChemistryParallelCleverly prepared mixturesRecover most active compounds
CAMD Steps
Determine Structure of Guest or HostBuild a model of binding siteSearch databases for new guests (or
hosts)Dock new guests and binding sitesPredict binding constants or activitySynthesize guests or hosts
Acetylcholine Esterase
Neurotransmitter recycling
Design drug that acts like nicotinamide
Acetylcholine Esterase
Brookhaven protein database
Human disease- molecular biology databasesSWISS-PROTOMIMGenBankMEDLINE
Structure Searches
2D Substructure searches3D Substructure searches3D Conformationally flexible searches
cfs
2D Substructure Searches
Functional groupsConnectivity
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 RelationshipsDefine ranges for
distances and anglesStored 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
3D Structural Databases
Compendium of Medicinal Chemistry6,000 (ISIS)
NCI-3D Chemotherapy Screening250,000 (WWW)
Cambridge Structural Database X-ray128,000 (Quest, ISIS)
CRC Properties of Organic Compounds28,000 (Windows, Microsoft Access)
Conformationally Flexible Searches
Rotate around all freely rotatable bonds
Many conformationsLow energy penaltyGet many more hitsGuests adapt to hosts
and Hosts adapt to guests
O
Cl
H
O
Cl
H
3.2Å
4.3Å
Guest-Host Chemistry
N
N
S
N
N
N
N
N
S
N
N
N
S
N
N
S
N
O
O
Pepcid
Tagamet
N
S
N
S
N
N
N
+
O
O
Axid
O
N
S
N
N
N
+
O
O
Zantac
Binding Site Model
Using experimental binding constantsBuild interaction model of host binding
siteUse 3D database searching to find
other good guests
Nizatidine-Guests
N
O
H
C
H
3
O
H
O
H
pyridoxine (Vitamin B6)
N
N
N
N
O
C
H
3
O
C
H
3
C
H
3
caffeine
N
H
N
H
N
H
2
O
O
luminol
O
H
O
H
O
H
pyrogallol
O
H
O
H
O
H
O
H
O
H
O
H
sorbitol
N
H
2
O
O
phenylalanine
N
H
2
O
N
O
H
tryptophan
Binding Model
Pharmacophore
O
H
O
H
6.52 - 7.52 Å
32.8 - 52.8 °
Computer Aided Molecular Design
Quantitative Structure Activity Relationships- QSAR
Quantitative Structure Property Relationships- QSPR
Structure-Activity Relationships
Determine binding constantsNMRFluorescenceUV/VisibleTitration CalorimetryHPLC
QSAR
Uncover important factors in chemical reactivity
Based on Hammett Relationships in Organic Chemistry
Medicinal ChemistryGuest-Host ChemistryEnvironmental Chemistry
pKa Substituted Benzoic Acids
log Ka - log KaH = σK aH is the reference compound-
unsubstituted
-0.6-0.4-0.2
00.20.40.60.8
1
-1 -0.5 0 0.5 1sigma
log Ka
O
O
H
R1
Hammett σ ConstantsGroup σp σm-NH 2 -0.57 -0.09-OH -0.38 0.13-OCH3 -0.28 0.10-CH 3 -0.14 -0.06-H 0 0-F 0.15 0.34-Cl 0.24 0.37-COOH 0.44 0.35-CN 0.70 0.62-NO 2 0.81 0.71
Growth Inhibition for Hamster Ovary Cancer Cells
N
(CH2CH2Cl)2R
y = -2.5 σ - 0.21R2 = 0.97
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
-1 -0.5 0 0.5 1
σ
log(1/IC50)
-NO2
-NH3+
QSAR Descriptors and Datasets
MedChem Project- Pomona CollegeLeo HanschWWW versionCurriculum materials
Reaction Databases
600,000 chemical reactionsSynthetic routesChemInform - ReactsAccess by substructure and bond
rearrangmentsMost used database by students
Information Rich Curriculum
Independent and CreativeGather Information EfficientlyJudge the Quality of the InformationUse information to Form Policies and
Make Decisions
Information Rich Curriculum
Massive amount of informationDatabase technologyCentral to mission of the courseStudents are active participants
Gathering and Assessing QualitySimulation