computer aided molecular design a strategy for meeting the challenges we face
TRANSCRIPT
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
Ste
ric
Energ
y (
kca
l/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
Acetylcholine Esterase
RCSB Protein Data Bank (PDB)
Human disease- molecular biology databases» SWISS-PROT» OMIM» GenBank» MEDLINE
Acetylcholine Esterase
CH3 N
CH3
CH3
CH2CH2O C
O
CH3CH3 N
CH3
CH3
CH2CH2OH
O C
O
CH3 H+
OH2
+ ++
+ +
N
N+
H
Nicotine
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 compound-
unsubstituted
-0.8
-0.6
-0.4-0.2
0
0.2
0.40.6
0.8
1
-1 -0.5 0 0.5 1
sigma
log Ka
O
O
H
R1
Hammett Constants
Group p m
-NH 2 -0.57 -0.09-OH -0.38 0.13-OCH3 -0.28 0.10-CH3 -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-NO2 0.81 0.71
Sigma-rho plots
One application of QSPR Activity = + constant Y = mx + b descriptor : slope
Growth Inhibition for Hamster Ovary Cancer Cells
N
(CH2CH2Cl)2R
y = -2.5 - 0.21
R2 = 0.97
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
-1 -0.5 0 0.5 1
log(1
/IC
50)
-NO2
-NH3+
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
H O2
QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones,
and Ethers with Tadpoles
Compound log(1/C) log PCH3OH 0.30 -1.27C2H5OH 0.50 -0.75CH3COCH3 0.65 -0.73(CH3)2CHOH 0.90 -0.36(CH3)3COH 0.90 0.07CH3CH2CH2OH 1.00 -0.23CH3COOCH3 1.10 -0.38C2H5COCH3 1.10 -0.27HCOOC2H5 1.20 -0.38C2H5COC2H5 1.20 0.59(CH3)2C(C2H5)OH 1.20 0.59CH3(CH2)3OH 1.40 0.29(CH3)2CHCH2OH 1.40 0.16CH3COOC2H5 1.50 0.14C2H5COC2H5 1.50 0.31CH3(CH2)4OH 1.60 0.81CH3CH2CH2COCH3 1.70 0.31CH3COOCH2C2H5 2.00 0.66C2H5COOC2H5 2.00 0.66(CH3)2CHCOOC2H5 2.20 1.05
QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones,
and Ethers with Tadpoles
y = 0.7315x + 1.2211
R2 = 0.7767
0
0.5
1
1.5
2
2.5
-2 -1 0 1 2log P
log
(1/C
) R = 0.881n = 20
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 + 0.50n = 10 r = 0.995
log Plog P
hydrophillic
hydrophobic
ethanol -.75
pentanol 0.81
isopropanol -0.36n-propanol -0.23
benzene 2.13
methanol -1.27
tetraethylammonium iodide -2.82
phenylalanine -1.38
alanine -2.85
pyridine 0.64
imidazole -0.08
diethylamine 0.45
butylamine 0.85
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 waterdesolG(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
EVdW,ij = - Arij6 +
Brij
12
Molecular Refractivity, MR
Molecular Refractivity, MR» size and polarizability» local non-lipophilic interactions
Lorentz-Lorentz equation:
MR = (n2 - 1)(n2 + 2)
MW
d
Group Additive Properties, GAPs
Substituent Volume (SA) MR Rot Bonds
-H 1.48 0.10 0 (reference) 0
-CH3 18.78 0.57 0.56 0
-CH2CH3 35.35 1.03 1.02 1
-CH2CH2CH3 51.99 1.5 1.55 2
-CH(CH3)2 51.33 1.5 1.53 1
-CH2CH2CH2CH3 68.63 1.96 2.13 3
-C(CH3)3 86.99 1.96 1.98 1
-C6H5 72.20 2.54 1.96 1 -F 7.05 0.10 0.14 0
-Cl 15.85 0.60 0.71 0