This document discusses the history of applying mathematics to chemistry. It notes that in 1830, Augusto Compte argued that using mathematics in chemistry was "profoundly irrational." However, in 1808, Louis Joseph Gay-Lussac stated that the application of calculation to chemistry was not far off. The document provides these two quotes contrasting early views on quantitative chemistry.

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«
, »
. .
, .

2. F T ra n sf o F T ra n sf o
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(1929 – 1983)

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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
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George S. Hammond:
-
, .“
(Norris Award Lecture, 1968)

5. F T ra n sf o F T ra n sf o
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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
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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
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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
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!)
,
,
-
”c

9. F T ra n sf o F T ra n sf o
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High throughput screening
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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
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DOCKING OF CONSTRUCTED
SELECTIVE ANTAGONIST OF mGluR1

11. F T ra n sf o F T ra n sf o
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LUDI, LeapFrog, LigBuilder
Grow Link
)
)

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QSAR
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(Quantitative Structure-Activity Relationship)
QSAR
, ,
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QSAR -
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(
)
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.

13. F T ra n sf o F T ra n sf o
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QSAR
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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
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Quantitative Structure – Activity Relationship
1D 3H7O2N
», «CODESSA»,
H O
«HQSAR», «DRAGON»
2D H3C
NH2 OH
CoMFA, CoMSiA, HASL,
3D
4D

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Structure-Activity(Property) Relationships
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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
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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
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«…
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».
».
Hermann L., 1868. Brown A., 1868
( ) ( )

22. F T ra n sf o F T ra n sf o
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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
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2.0
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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
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CoMFA
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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
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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
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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
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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
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.
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
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.