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 Recognition
Hydrogen bonding
•Charge-charge interactions (salt bridges)
• Dipole-dipole
 p – p interactions (aromatic)
• Hydrophobic (like dissolves like)



H


Hosts:  cyclodextrin
OH
O
O
HO
OH
O
HO
OH
OH
O
O
HO
HO
OH
O
O
HO
O
HO
HO
HO
O
OH
HO
HO
HO
O
O
HO O
HO
HO
O
OH
O
Hexasulfo-calix[6]arenes
O
O S O
O
O
O
S
S
O
OH
O
OH
OH
OH
OH
OH
O
O
O
O
S
S
O
O
O S 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
[F,Cl,Br,I]
» Halogen substituted
aromatic and a
carboxyl group
O
O
2D Substructure Searches
Cl

Query:
Cl
O
» Halogen substituted
aromatic and a
carboxyl group
O
O
O
N
O
O
N
O
N
F
O
I
N
N
O
N
F
F
O
3D Substructure Searches
A



Spatial
Relationships
Define ranges for
distances and
angles
Stored conformation
O(s1)
C (u)
O(s1)
3.3 - 4.3 Å
O
6.8 - 7.8 Å
» usually lowest energy
3.6 - 4.6 Å
[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
3.2Å
Cl
O H
Cl
4.3Å
O H
Conformationally Flexible Searches
3.2Å
Cl
O H
Cl
4.3Å
O H
6

Small energy penalty
Steric Energy (kcal/mol)
5
4
3
2
1
0
0
60
120
180
Dihedral angle
240
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
N
N
N
Losartan
N
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

Acetylcholine Esterase
RCSB Protein
Data Bank (PDB)
 Human diseasemolecular biology
databases

» SWISS-PROT
» OMIM
» GenBank
» MEDLINE
Acetylcholine Esterase
CH3
H3C + N
CH3
CH3
O
CH2 CH2 O
C
CH3
H3C
+N
H
CH2 CH2 O
O
+
CH3
+HO
2
N
Nicotine
+
N
H
O
C
CH3
+
+
H
Hammett Relationships
pKa of benzoic acids
 Effect of electron withdrawing and
donating groups
 based on rG = - RT ln Keq

pKa Substituted Benzoic Acids
log Ka - log KaH = 
 K aH is the reference compound1
log Ka
unsubstituted
0.8

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  Constants
Group
-NH 2
-OH
-OCH 3
-CH 3
-H
-F
-Cl
-COOH
-CN
-NO 2
p
m
-0.57
-0.38
-0.28
-0.14
0
0.15
0.24
0.44
0.70
0.81
-0.09
0.13
0.10
-0.06
0
0.34
0.37
0.35
0.62
0.71
Sigma-rho plots
One application of QSPR
 Activity = r  + constant
 Y = mx + b
 : descriptor
 r : slope

Growth Inhibition for Hamster Ovary Cancer
Cells
N (CH2CH2Cl)2
R
1.5
-NH3+
y = -2.5
1
2
R = 0.97
0.5
log(1/IC50)
 - 0.21
0
-1
-0.5
-0.5
0
0.5
1
-1
-1.5
-NO2
-2
-2.5

Octanol-Water Partition
Coefficients


P = C(octanol)
C(water)
log P
like rG = - RT ln Keq


Hydrophobic hydrophilic character
P increases then
more hydrophobic
Octanol
H2O
QSAR and log P
Isonarcotic Activity of Esters, Alcohols, Ketones, and
Ethers with Tadpoles
Compound
CH3 OH
C2 H5 OH
CH3 COCH3
(CH 3 ) 2 CHOH
(CH 3 ) 3 COH
CH3 CH2 CH2 OH
CH3 COOCH3
C2 H5 COCH3
HCOOC2 H5
C2 H5 COC2 H5
(CH 3 ) 2 C(C 2 H5 )OH
CH3 (CH 2 ) 3 OH
(CH 3 ) 2 CHCH 2 OH
CH3 COOC2 H5
C2 H5 COC2 H5
CH3 (CH 2 ) 4 OH
CH3 CH2 CH2 COCH3
CH3 COOCH2 C2 H5
C2 H5 COOC2 H5
(CH 3 ) 2 CHCOOC2 H5
log(1/C)
0.30
0.50
0.65
0.90
0.90
1.00
1.10
1.10
1.20
1.20
1.20
1.40
1.40
1.50
1.50
1.60
1.70
2.00
2.00
2.20
log P
-1.27
-0.75
-0.73
-0.36
0.07
-0.23
-0.38
-0.27
-0.38
0.59
0.59
0.29
0.16
0.14
0.31
0.81
0.31
0.66
0.66
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

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
log P
hydrophobic
benzene 2.13
pentanol 0.81
n-propanol -0.23
isopropanol -0.36
ethanol -.75
methanol -1.27
hydrophillic
butylamine 0.85
pyridine 0.64
diethylamine 0.45
imidazole -0.08
phenylalanine -1.38
tetraethylammonium iodide -2.82
alanine -2.85
Estimating log P
M (aq) –> M (octanol) PG = -RT ln P
 M (aq) –> M (g)
desolG(aq)
 M (octanol) –> M (g)
desolG(octanol)
 PG = desolG(aq) – desolG(octanol)
 PG = Fh2o - Foct
 log P = – (1/2.303RT) Fh2o - Foct

» 1/2.303RT = – 0.735
Solvent-Solute Interaction

desolG(aq) = Fh2o
» Free Energy of desolvation in water
» desolG(aq) = -RT ln KHenry’s

desolG(octanol) = Foct
» Free Energy of desolvation in octanol
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
Atomic Polarizability, Apol

Atomic Polarizability
» Ease of distortion of electron clouds
» sum of Van der Waals A coefficients
A
B
EVdW,ij = - r 6 + r 12
ij
ij
Molecular Refractivity, MR

Molecular Refractivity, MR
» size and polarizability
» local non-lipophilic interactions
Lorentz-Lorentz equation:
2
(n - 1) MW
MR = (n2 + 2)  d 


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