SIMPLE

1. CADD
BY-KIRAN C.RODGE

2. Structural Biology
 Fastest growing
area of biology
 Protein and
nucleic acid
structure and
function
 How proteins
control living
processes

3. Medicinal Chemistry
 Organic Chemistry
 Applied to disease
 Example: design
new enzyme
inhibitor drugs
– doxorubicin
(anti-cancer)

4. Pharmacology
 Biochemistry of Human Disease
 Different from Pharmacy: distribution of
pharmaceuticals, drug delivery systems

5. 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)

6. Principles
 Structure-Function Relationships
 Binding
» Step 1: Biochemical Mechanism
» Step 2: Understand and control
macromolecular binding

7. Binding
 Binding interactions
are how nature
controls processes
in living cells
 Enzyme-substrate
binding leads to
catalysis
 Protein-nucleic acid
binding controls
protein synthesis

8. 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

9. Molecular Recognition
Hydrogen bonding
•Charge-charge interactions (salt bridges)
•Dipole-dipole
 p – p interactions (aromatic)
• Hydrophobic (like dissolves like)
H






10. Hosts:  cyclodextrin
O
HO
O
OH
OH
O
HO
O
HO
OH
O
HO
O
HO
OH
O
HO
O HO
OH
O HO
O
HO
HO
O
HO
O
OH
HO
O
HO
O
OH
HO

11. Hexasulfo-calix[6]arenes
OH
OH
OH
OH
OH
OH
S
S
S
S
S
S
O
O
O
O
O
O
O
O
O
OO
O
O
O
O
O
O
O

12. 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

13. 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

14. 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

15. CAMD
 Computational techniques to guide
chemical intuition
 Design new hosts or guests
» Enzyme inhibitors
» Clinical analytical reagents
» Catalysts

16. 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

17. Structure Searches
 2D Substructure searches
 3D Substructure searches
 3D Conformationally flexible searches
» cfs

18. 2D Substructure Searches
 Functional groups
 Connectivity
» Halogen substituted
aromatic and a
carboxyl group
[F,Cl,Br,I] O
O

19. 2D Substructure Searches
 Query:
» Halogen substituted
aromatic and a
carboxyl group
N
O O
Cl
OO
Cl
NN
N
O O
F
F
O
F
O
O
N
I
O
N

20. 3D Substructure Searches
 Spatial
Relationships
 Define ranges for
distances and
angles
 Stored conformation
» usually lowest energy
C(u)
O(s1)
O(s1)
A
A
[O,S]
O
3.6 - 4.6 Å
3.3 - 4.3 Å
6.8 - 7.8 Å

21. 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
OCl H
O
Cl
H
3.2Å
4.3Å

22. Conformationally Flexible Searches
OCl H
O
Cl
H
3.2Å
4.3Å
360300240180120600
0
1
2
3
4
5
6
Dihedral angle
StericEnergy(kcal/mol)
 Small energy penalty

23. 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
N
N
Cl
O
N N
N N
Losartan

24. Computer Aided Molecular
Design
Quantitative Structure Activity Relationships-
QSAR
Quantitative Structure Property Relationships-
QSPR

25. Introduction
 Uncover important factors in chemical
reactivity
 Based on Hammett Relationships in
Organic Chemistry
 Medicinal Chemistry
 Guest-Host Chemistry
 Environmental Chemistry

26. 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

27. 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

28. Acetylcholine Esterase
 Neurotransmitter
recycling
 Design drug that
acts like nicotine

29. Acetylcholine Esterase
 RCSB Protein
Data Bank (PDB)
 Human disease-
molecular biology
databases
» SWISS-PROT
» OMIM
» GenBank
» MEDLINE

30. Acetylcholine Esterase
CH3 N
CH3
CH3
CH2CH2O C
O
CH3
CH3
N
CH3
CH3
CH2
CH2
O
H
O C
O
CH3
H
+
OH2
+ +
+
+ +
N
N
+
H
Nicotine

31. Hammett Relationships
 pKa of benzoic acids
 Effect of electron withdrawing and
donating groups
 based on rG = - RT ln Keq

32. 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
0.4
0.6
0.8
1
-1 -0.5 0 0.5 1
sigma
log Ka
OO
H
R1

33. Hammett  Constants
Group p m
-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
-NO2 0.81 0.71

34. Sigma-rho plots
 One application of QSPR
 Activity = r  + constant
 Y = mx + b
 : descriptor
 r : slope

35. Growth Inhibition for Hamster Ovary Cancer
Cells
N (CH2CH2Cl)2
R
y = -2.5 - 0.21
R
2
= 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/IC50)
-NO2
-NH3
+

36. 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

37. QSAR and log P
Isonarcotic Activity of Esters, Alcohols, Ketones, and
Ethers with Tadpoles
Compound log(1/C) log P
CH3 OH 0.30 -1.27
C2 H5 OH 0.50 -0.75
CH3 COCH3 0.65 -0.73
(CH3 )2 CHOH 0.90 -0.36
(CH3 )3 COH 0.90 0.07
CH3 CH2 CH2 OH 1.00 -0.23
CH3 COOCH3 1.10 -0.38
C2 H5 COCH3 1.10 -0.27
HCOOC2 H5 1.20 -0.38
C2 H5 COC2 H5 1.20 0.59
(CH3 )2 C(C2 H5 )OH 1.20 0.59
CH3 (CH2 )3 OH 1.40 0.29
(CH3 )2 CHCH2 OH 1.40 0.16
CH3 COOC2 H5 1.50 0.14
C2 H5 COC2 H5 1.50 0.31
CH3 (CH2 )4 OH 1.60 0.81
CH3 CH2 CH2 COCH3 1.70 0.31
CH3 COOCH2 C2 H5 2.00 0.66
C2 H5 COOC2 H5 2.00 0.66
(CH3 )2 CHCOOC2 H5 2.20 1.05

38. 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 2
log P
log(1/C)
R = 0.881
n = 20

39. 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

40. log P
hydrophillic
hydrophobic
ethanol -.75
pentanol 0.81
isopropanol -0.36
n-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

41. 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

42. 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

43. 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

44. Atomic Polarizability, Apol
 Atomic Polarizability
» Ease of distortion of electron clouds
» sum of Van der Waals A coefficients
EVdW,ij = -
A
rij
6 +
B
rij
12

45. Molecular Refractivity, MR
 Molecular Refractivity, MR
» size and polarizability
» local non-lipophilic interactions
Lorentz-Lorentz equation:
MR =
(n2
- 1)
(n2
+ 2) 







MW
d

46. Group Additive Properties,
GAPs
Substituent Volume (SA) MR p 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