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Computer Aided Molecular Design

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Computer Aided Molecular
Design
A Strategy for Meeting the
Challenges We Face
An Organized Guide
Build Chemical Insight
пЃ¬ Discover new molecules
пЃ¬ Predict their properties
пЃ¬
Working at the Intersection
Structural Biology
пЃ¬ Biochemistry
пЃ¬ Medicinal Chemistry
пЃ¬ Toxicology
пЃ¬ Pharmacology
пЃ¬ Biophysical Chemistry
пЃ¬ Information Technology
пЃ¬
Structural Biology
Fastest growing
area of biology
пЃ¬ Protein and
nucleic acid
structure and
function
пЃ¬ How proteins
control living
processes
пЃ¬
Medicinal Chemistry
пЃ¬
пЃ¬
пЃ¬
Organic Chemistry
Applied to disease
Example: design
new enzyme
inhibitor drugs
– doxorubicin
(anti-cancer)
Pharmacology
пЃ¬
Biochemistry of Human Disease
пЃ¬
Different from Pharmacy: distribution of
pharmaceuticals, drug delivery systems
New Ideas From Nature
пЃ¬
пЃ¬
Natural Products
Chemistry
Chemical Ecology
В» During the next two
decades: the major
activity in organismal
biology
пЃ¬
Examples: penicillin,
taxol (anti-cancer)
Working at the Intersection
Structural Biology
пЃ¬ Biochemistry
пЃ¬ Medicinal Chemistry
пЃ¬ Toxicology
пЃ¬ Pharmacology
пЃ¬ Biophysical Chemistry
пЃ¬ Information Technology
пЃ¬
Principles
Structure-Function Relationships
пЃ¬ Binding
пЃ¬
В» Step 1: Biochemical Mechanism
В» Step 2: Understand and control
macromolecular binding
Binding
пЃ¬
пЃ¬
пЃ¬
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
пЃ¬ Binding
пЃ¬
В» Understand and control binding ->disease
пЃ¬
Molecular Recognition
В» How do enzymes recognize and bind the
proper substrates
пЃ¬
Guest-Host Chemistry
В» Molecular Recognition in Cyclodextrins
Molecular Recognition
пЃ¬Hydrogen bonding
•Charge-charge interactions (salt bridges)
• Dipole-dipole
 p – p interactions (aromatic)
• Hydrophobic (like dissolves like)
пЃ¤пЂ­
пЃ¤пЂ­
пЃ¤пЂ«
H
пЃ¤пЂ­
пЃ¤пЂ­
Hosts: пЃўпЂ­ cyclodextrin
OH
O
O
HO
O
OH
HO
OH
OH
O
HO
HO
O
OH
O
O
HO
O
HO
HO
HO
O
OH
HO
HO
HO
O
O
HO
HO
HO
O
OH
O
O
Hexasulfo-calix[6]arenes
O
O
S
O
O
O
O
S
S
O
O
OH
OH
OH
OH
OH
OH
O
O
O
O
S
S
O
O
O
S
O
O
O
Molecular Design
Originated in Drug Design
пЃ¬ Agricultural, Veterinary, Human Health
пЃ¬ Guest - Host Chemistry
пЃ¬ Ligands for Inorganic Complexes
пЃ¬ Materials Science
пЃ¬
В» Polymer Chemistry
В» Supramolecular Chemistry
В» Semi-conductors, nonlinear phenomena
Information Technology
Chemical Abstracts Service registered
over one million new compounds last
year
пЃ¬ Expected to increase every year
пЃ¬ Need to know the properties of all
known compounds:
пЃ¬
В» pharmaceutical lead compounds
В» environmental behavior
Information Technology
Store and Retrieve
пЃ¬ Molecular Structures and Properties
пЃ¬ Efficient Retrieval Critical Step
пЃ¬ Multi-million $ industry
пЃ¬ Pharmaceutical Industry
пЃ¬
В» $830 million to bring a new drug to market
В» Need to find accurate information
В» Shorten time to market, minimize mistakes
CAMD
Computational techniques to guide
chemical intuition
пЃ¬ Design new hosts or guests
пЃ¬
В» Enzyme inhibitors
В» Clinical analytical reagents
В» Catalysts
CAMD Steps
Determine Structure of Guest or Host
пЃ¬ Build a model of binding site
пЃ¬ Search databases for new guests (or
hosts)
пЃ¬ Dock new guests and binding sites
пЃ¬ Predict binding constants or activity
пЃ¬ Synthesize guests or hosts
пЃ¬
Structure Searches
2D Substructure searches
пЃ¬ 3D Substructure searches
пЃ¬ 3D Conformationally flexible searches
пЃ¬
В» cfs
2D Substructure Searches
пЃ¬
пЃ¬
Functional groups
Connectivity
[ F,C l,B r,I]
В» Halogen substituted
aromatic and a
carboxyl group
O
O
2D Substructure Searches
Cl
пЃ¬
Query:
Cl
В» Halogen substituted
aromatic and a
carboxyl group
O
O
O
O
N
O
O
N
O
N
F
O
I
N
N
O
N
F
F
O
3D Substructure Searches
A
пЃ¬
пЃ¬
пЃ¬
Spatial
Relationships
Define ranges for
distances and
angles
Stored conformation
O ( s1 )
C (u )
O( s1 )
3.3 - 4.3 Г…
O
6.8 - 7.8 Г…
В» usually lowest energy
3.6 - 4.6 Г…
[O ,S ]
A
Conformationally Flexible Searches
пЃ¬
пЃ¬
пЃ¬
пЃ¬
пЃ¬
Rotate around all
freely rotatable
bonds
Many conformations
Low energy penalty
Get many more hits
Guests adapt to
hosts and Hosts
adapt to guests
3.2Г…
Cl
O
H
Cl
4.3Г…
O
H
Conformationally Flexible Searches
3.2Г…
Cl
O
H
Cl
4.3Г…
O
H
6
пЃ¬
Small energy penalty
S te r i c E ne r gy ( k c a l / m ol )
5
4
3
2
1
0
0
60
120
180
Dihe dral a ngle
240
300
360
Angiotensin Converting Enzyme
Zn containing protease
пЃ¬ Converts Angiotensin I
пЃ¬ Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
O
пЃ¬ -> Angiotensin II
Cl
пЃ¬
В» Raises blood pressure
В» Vascular constriction
В» Restricts flow to kidneys
В» Diminishing fluid loss
N
N
N
N
N
Losartan
N
Computer Aided Molecular
Design
Quantitative Structure Activity RelationshipsQSAR
Quantitative Structure Property RelationshipsQSPR
Introduction
Uncover important factors in chemical
reactivity
пЃ¬ Based on Hammett Relationships in
Organic Chemistry
пЃ¬ Medicinal Chemistry
пЃ¬ Guest-Host Chemistry
пЃ¬ Environmental Chemistry
пЃ¬
CAMD
Determine Structure of Guest or Host
пЃ¬ Build a model of binding site
пЃ¬ Search databases for new guests (or hosts)
пЃ¬ Dock new guests and binding sites
пЃ¬ Predict binding constants or activity
пЃ¬ Synthesize guests or hosts
пЃ¬
Outline
Hammett Relationships
пЃ¬ log P : Octanol-water partition
coefficients
пЃ¬
В» uses in Pharmaceutical Chemistry
В» uses in Environmental Chemistry
В» uses in Chromatography
Other Descriptors
пЃ¬ Multivariate Least Squares
пЃ¬ Nicotinic Agonists - Neurobiology
пЃ¬
Acetylcholine Esterase
Neurotransmitter
recycling
пЃ¬ Design drug that
acts like nicotine
пЃ¬
Acetylcholine Esterase
RCSB Protein
Data Bank (PDB)
пЃ¬ Human diseasemolecular biology
databases
пЃ¬
В» SWISS-PROT
В» OMIM
В» GenBank
В» MEDLINE
Acetylcholine Esterase
C H3
H3C
+N
C H3
C H3
O
C H2 C H2 O
+
C
C H3
H3C
+N
O
H
C H2 C H2 O
+
C H3
H2 O
N
Nicotine
+
N
H
O
C
C H3
+
+
H
Hammett Relationships
pKa of benzoic acids
пЃ¬ Effect of electron withdrawing and
donating groups
пЃ¬ based on пЃ„rG = - RT ln Keq
пЃ¬
pKa Substituted Benzoic Acids
log Ka - log KaH = пЃі
пЃ¬ K aH is the reference compound1
log Ka
unsubstituted
0.8
пЃ¬
O
O
H
-1
R1
-0.5
0.6
0.4
0.2
0
-0.2 0
-0.4
-0.6
-0.8
0.5
1
sigma
Hammett пЃі Constants
Group
пЃіp
пЃіm
-NH 2
-OH
-OCH 3
-0.57
-0.09
-CH 3
-H
-F
-Cl
-COOH
-CN
-NO 2
-0.14
-0.38
-0.28
0
0.15
0.24
0.44
0.70
0.81
0.13
0.10
-0.06
0
0.34
0.37
0.35
0.62
0.71
Sigma-rho plots
One application of QSPR
пЃ¬ Activity = r пЃі + constant
пЃ¬ Y = mx + b
пЃ¬ пЃі: descriptor
пЃ¬ r : slope
пЃ¬
Growth Inhibition for Hamster Ovary Cancer
Cells
N (CH 2 CH 2 Cl) 2
R
1. 5
-NH3+
y = -2. 5
1
R
2
пЃі
- 0.21
= 0. 97
l o g (1 / I C5 0 )
0. 5
0
-1
-0.5
-0.5
0
0. 5
1
-1
-1.5
-NO2
-2
-2.5
пЃі
Octanol-Water Partition
Coefficients
пЃ¬
пЃ¬
P = C(octanol)
C(water)
log P
like пЃ„rG = - RT ln Keq
пЃ¬
пЃ¬
Hydrophobic hydrophilic character
P increases then
more hydrophobic
Octanol
H 2O
QSAR and log P
Isonarcotic Activity of Esters, Alcohols, Ketones, and
Ethers with Tadpoles
Compound
CH 3 OH
log(1/C)
0.30
log P
-1.27
C 2 H 5 OH
0.50
-0.75
CH 3 COCH 3
(CH 3 ) 2 CHOH
0.65
-0.73
0.90
-0.36
(CH 3 ) 3 COH
CH 3 CH 2 CH 2 OH
0.90
0.07
1.00
-0.23
CH 3 COOCH 3
C 2 H 5 COCH 3
1.10
-0.38
1.10
-0.27
HCOOC 2 H 5
C 2 H 5 COC 2 H 5
1.20
-0.38
1.20
0.59
(CH 3 ) 2 C(C 2 H 5 )OH
CH 3 (CH 2 ) 3 OH
1.20
0.59
1.40
0.29
(CH 3 ) 2 CHCH 2 OH
CH 3 COOC 2 H 5
1.40
0.16
1.50
0.14
C 2 H 5 COC 2 H 5
1.50
0.31
CH 3 (CH 2 ) 4 OH
CH 3 CH 2 CH 2 COCH 3
CH 3 COOCH 2 C 2 H 5
1.60
0.81
1.70
0.31
2.00
0.66
C 2 H 5 COOC 2 H 5
(CH 3 ) 2 CHCOOC 2 H 5
2.00
0.66
2.20
1.05
QSAR and log P
Isonarcotic Activity of Esters, Alcohols, Ketones, and
Ethers with Tadpoles
log(1/C)
2.5
y = 0.7315x + 1.2211
2
R2 = 0.7767
R = 0.881
1.5
n = 20
1
0.5
0
-2
-1
0
log P
1
2
Isonarcotic Activity of Esters, Alcohols,
Ketones, and Ethers with Tadpoles
пЃ¬
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
пЃ¬
n = 10
r = 0.995
log P
hydrophobic
benzene 2.13
pentanol 0.81
n-propanol -0.23
isopropanol -0.36
ethanol -.75
methanol -1.27
butylamine 0.85
pyridine 0.64
diethylamine 0.45
imidazole -0.08
phenylalanine -1.38
hydrophillic
tetraethylammonium iodide -2.82
alanine -2.85
Estimating log P
M (aq) –> M (octanol) PG = -RT ln P
 M (aq) –> M (g)
пЃ„desolG(aq)
 M (octanol) –> M (g)
пЃ„desolG(octanol)
 PG = desolG(aq) – desolG(octanol)
пЃ¬ пЃ„PG = Fh2o - Foct
 log P = – (1/2.303RT) Fh2o - Foct
пЃ¬
» 1/2.303RT = – 0.735
Solvent-Solute Interaction
пЃ¬
пЃ„desolG(aq) = Fh2o
В» Free Energy of desolvation in water
» desolG(aq) = -RT ln KHenry’s
пЃ¬
пЃ„desolG(octanol) = Foct
В» Free Energy of desolvation in octanol
Descriptors
Molar Volume, Vm
пЃ¬ Surface area
пЃ¬ Rotatable Bonds, Rotbonds, b_rotN
пЃ¬ Atomic Polarizability, Apol
пЃ¬
В» Ease of distortion of electron clouds
В» sum of Van der Waals A coefficients
пЃ¬
Molecular Refractivity, MR
В» size and polarizability
В» local non-lipophilic interactions
Atomic Polarizability, Apol
пЃ¬
Atomic Polarizability
В» Ease of distortion of electron clouds
В» sum of Van der Waals A coefficients
A
B
EVdW,ij = - r 6 + r 12
ij
ij
Molecular Refractivity, MR
пЃ¬
Molecular Refractivity, MR
В» size and polarizability
В» local non-lipophilic interactions
Lorentz-Lorentz equation:
2
(n - 1) пѓ¦пѓ§MWпѓ¶пѓ·
MR = (n2 + 2) пѓ§ d пѓ·
пѓЁ
пѓё
Group Additive Properties,
GAPs
Substituent
Volume (SA)
-H
1.48
-CH3
18.78
-CH2CH3
35.35
-CH2CH2CH3
51.99
-CH(CH3)2
51.33
-CH2CH2CH2CH3
68.63
-C(CH3)3
86.99
-C6H5
72.20
-F
7.05
-Cl
15.85
MR
p
Rot Bonds
0.10 0 (reference)
0
0.57
0.56
0
1.03
1.02
1
1.5
1.55
2
1.5
1.53
1
1.96
2.13
3
1.96
1.98
1
2.54
1.96
1
0.10
0.14
0
0.60
0.71
0
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