AACIMP 2009 Summer School lecture by Victor Kuzmin. "Environmental Chemoinfornatics" course.

1. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
1
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
«
, »
. .
, .

2. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
2
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
(1929 – 1983)

3. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
3
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
Augusto Compte (1798-1857)
in 1830:
"…every attempt to employ mathematical
methods in the study of chemical
questions must be considered profoundly
irrational and contrary to the spirit of
chemistry. . ."
Louis Joseph Gay-Lussac (1778-1850)
in 1808:
"We are perhaps not far removed from the
time when we shall be able to submit the bulk
of chemical phenomena to calculation"

4. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
4
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
George S. Hammond:
-
, .“
(Norris Award Lecture, 1968)

5. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
5
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
Weininger :
"There are 10180 possible drugs,
1018 likely drugs,
107 known compounds,
106 commercially available compounds,
106 compounds in corporate databases,
104 compounds in drug databases,
103 commercial drugs and
102 profitable drugs "
J. Chem. Inf. Comput. Sci., 37, 138 (1997)

6. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
6
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
25%
10%
50%
15%
~ 1000 .$
Ooms, F. Curr. Med. Chem. 2000, 7, 141-158
6

7. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
7
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
45% -
28% -
11% -
5% -
2% -
14% -
de novo
HOOC COOH
H3C N CH3

8. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
8
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
!)
,
,
-
”c

9. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
9
re
re
he
he
k
k
lic
lic
High throughput screening
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
HTS robot Compound transfer robot
“High throughput screening”- -
, “ ”. -
-
.
HTS , -
, -
.
“ Facilities which normally only industry had can now increasingly
be found as well at universities”

10. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
10
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
DOCKING OF CONSTRUCTED
SELECTIVE ANTAGONIST OF mGluR1

11. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
11
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
LUDI, LeapFrog, LigBuilder
Grow Link
)
)

12. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
12
re
re
he
he
k
k
lic
lic
QSAR
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
(Quantitative Structure-Activity Relationship)
QSAR
, ,
.
QSAR -
, ,
(
)
.
.
.

13. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
13
re
re
he
he
k
k
lic
lic
QSAR
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
1815 – W. Black: ,
.
1863 – A. Cros: ,
.
1894 – E. Fisher: « –
».
1913 – P. Ehrilich: , .
1962 – . Hansch: – .
1964 – S.M. Free, J.W. Wilson:
.
1974 – B. Pullman, D. Pullman:
.
1988 – R.D. Cramer, D.E. Patterson: CoMFA –
1989 – “The International QSAR Society”
2007 – “The Cheminformatics and QSAR Society” (945 )
QSAR
Dorzolamide ( ),
Saquinavir, Indinavir, Ritonavir, Nelfinavir ( )
Phospholipase A2 inhibitors ( )

14. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
14
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
Quantitative Structure – Activity Relationship
1D 3H7O2N
», «CODESSA»,
H O
«HQSAR», «DRAGON»
2D H3C
NH2 OH
CoMFA, CoMSiA, HASL,
3D
4D

15. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
15
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c

16. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
16
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c

17. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
17
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
, . , HOMO,
, LUMO,
, .
.
, -
_
N
: C
N
, NN, HCCN, (2D- ) (3D- ),
C
CCCO, .
3D-
1D 2D 3D, 4D
_
-
_ 2D- 3D-
(
)
,

18. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
18
re
re
he
he
:
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
:
[Randic, ; Kier-Hall, ], [W]
, ,
, ,
,
:
, ,
( ),
,
,
, HOMO-LUMO- , ,
, ,
)
, ,
.
,
, .

19. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
19
re
re
he
he
k
k
Structure-Activity(Property) Relationships
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
Additive schemes:
A= Ai n (sum 1,2,. . . N) A = A0 + Ai n (sum 1,2,. . . N)
Hammett eq.: pK =
Hansch Approach (correlation of biological activity with lipophilicity,
Hammett and Taft constants of substituents) :
log(1/C) = k1 logP - k2 (logP)2 + k3 + k4 Es + k0
C. Hansch, T. Fujita J.Am.Chem.Soc. 1964, 86, 1616;
C. Hansch Acc. Chem. Res. 1969, 2, 232.
O
Anticonvulsant activity of 1,4-benzodiazepinones: NH
(R = Cl, Br, CN, NO2, CF3, N(CH3)2, SCH3, SEt, n-BuS, SOCH3)
R N
log(1/C) = 0.144 - 0.307 2 +1.291 + 4.558
Ph
n=10, r=0.87, s=0.47
E.J.Lien, R.C.H.Liao, H.G.Shinouda J.Pharm.Sci. 1979,
68, 463.

20. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
20
Structure-Activity(Property)
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
Relationships
Fragmental and subsructural approach:
Bioactivity(BA) = aA+bB+cC+. . . nN
Free-Wilson method (additivity approach):
Bioactivity(BA) = BA0+ BAip sip (sip = 1 or 0)
X
Antiadrenergic activity of substituted
N,N-dimethyl-a-bromophenylamines: Y CHCH2N(CH3)2
Br
Log(1/C) = -0.301 (m-F) + 0.207 (m-Cl) + 0.434(m-Br) +
0.579(m-I) + 0.454(m-CH3) +0.340(p-F) +0.768(p-Cl) +
1.02(p-Br) + 1.429(p-I) + 1.256(p-CH3) + 7.821
N = 22, r = 0.969, s = 0.194

21. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
21
re
re
he
he
k
k
lic
lic
C
C
w om
«… w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
«…
,
».
».
Hermann L., 1868. Brown A., 1868
( ) ( )

22. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
22
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
Randic Index ( )
CH3 C1
= ( i j)-1/2
bonds CH CH2 C2 C3
CH3 CH3 C5 C4
1 C1 C2 C3 C4 C5
1 3 3 2 C1 1 0 0 0
2 C2 1 1 0 1
4
1 1 C3 0 1 1 0
C4 0 0 1 0
C5 0 1 0 0
= 1/(3)1/2+1/(3)1/2+1/(6)1/2+1/(2)1/2=2.27

23. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
23
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
Hologram QSAR

24. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
24
re
re
he
he
CoMFA
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
Comparative Molecular Field Analysis

25. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
25
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c

26. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
26
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
INFORMATIO (Latina) – ", " ".
,
.
” / . /
.” / . /
– .” / / , .
======================================================
» ; =n
m
m1 m2 m3 …. mk ;
k n; mi mj = 0; mi = ni ; ni = n
i : pi = ni/n
:
I=- pi log2 pi
============================================================
:
MIN: M = m1 ; n = n1 ; p1 = 1 ; I = I` = 0
MAX: ni = 1 ; pi = 1/n ; I = log2 n ; I` = n log2 n

27. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
I 3 1 4 lb (1 4) 2 1 8 lb(1 8) 2,24 bit

28. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
28
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
” . .
. .
I=0 I 0
============================================================
,
, . .

29. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
29
re
re
he
he
k
k
lic
lic
C
C
w om w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
.
I(A) = lb(N/1), I(B) = lb(N/8), I(C) = lb(N/16), I(D) = lb(N/24)
N– .

30. F T ra n sf o F T ra n sf o
PD rm PD rm
Y Y
Y
Y
er
er
ABB
ABB
y
y
bu
bu
2.0
2.0
to
to
30
re
re
he
he
k
k
lic
lic
C
C
w om
, w om
w
w
w. w.
A B B Y Y.c A B B Y Y.c
.