Search and Structure Design of Physiologically Active Compounds
56
1 Ʉɭɡɶɦɢɧ ȼɢɤɬɨɪ ȿɜɝɟɧɶɟɜɢɱ Ɏɢɡɢɤɨɯɢɦɢɱɟɫɤɢɣ ɢɧɫɬɢɬɭɬ ɢɦ. Ⱥȼ. Ȼɨɝɚɬɫɤɨɝɨ ɇȺɇ ɍɤɪɚɢɧɵ, ɝ. Ɉɞɟɫɫɚ Ʌɟɬɧɹɹ ɲɤɨɥɚ «Ⱦɨɫɬɢɠɟɧɢɹ ɢ ɩɪɢɥɨɠɟɧɢɹ ɫɨɜɪɟɦɟɧɧɨɣ ɢɧɮɨɪɦɚɬɢɤɢ, ɦɚɬɟɦɚɬɢɤɢ ɢ ɮɢɡɢɤɢ» Click here to buy A B B Y Y P D F T r a n s f o r m e r 2 . 0 w w w . A B B Y Y . c o m Click here to buy A B B Y Y P D F T r a n s f o r m e r 2 . 0 w w w . A B B Y Y . c o m
description
AACIMP 2009 Summer School lecture by Victor Kuzmin. "Environmental Chemoinfornatics" course.
Transcript of Search and Structure Design of Physiologically Active Compounds
1
. . , .
«, »
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
2
(1929 – 1983)
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
3
"…every attempt to employ mathematicalmethods in the study of chemicalquestions must be considered profoundlyirrational and contrary to the spirit ofchemistry. . ."
Augusto Compte (1798-1857)in 1830:
Louis Joseph Gay-Lussac (1778-1850)in 1808:
"We are perhaps not far removed from thetime when we shall be able to submit the bulkof chemical phenomena to calculation"
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
4
George S. Hammond:
-, .“
(Norris Award Lecture, 1968)
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
5
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 and102 profitable drugs "
J. Chem. Inf. Comput. Sci., 37, 138 (1997)
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
6
6
Ooms, F. Curr. Med. Chem. 2000, 7, 141-158
~ 1000 . $
25%
10%
50%
15%
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
7
de novo
N
COOHHOOC
CH3CH3
45% -28% -11% -5% -2% -14% -
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
8
,,
-” c
!)
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
9
High throughput screening
HTS robot Compound transfer robot“High throughput screening”- -
, “ ”. --
.HTS , -
, -.
“ Facilities which normally only industry had can now increasinglybe found as well at universities”
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
10
DOCKING OF CONSTRUCTEDSELECTIVE ANTAGONIST OF mGluR1
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
11
LUDI, LeapFrog, LigBuilder
Grow Link
))
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
12QSAR
(Quantitative Structure-Activity Relationship)QSAR
, ,.
QSAR -, ,
()
.
..
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
13 QSAR
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, NelfinavirSaquinavir, Indinavir, Ritonavir, Nelfinavir ( )Phospholipase A2 inhibitorsPhospholipase A2 inhibitors ( )
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
14
», «CODESSA»,«HQSAR», «DRAGON»
CoMFA, CoMSiA, HASL,
1D
2D
3D
4D
NH2
OCH3
OH
H
3H7O2N
Quantitative Structure – Activity Relationship
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
15Clic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
16Clic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
17
,,
,
.
. , HOMO,LUMO,
.
_ , -
:, NN, HCCN,
CCCO, .(2D- ) (3D- ),
3D-
1D 2D 3D, 4D_
-
_ 2D- 3D- (
)
N
C
CN
,
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
18 :
[Randic, ; Kier-Hall, ], [W], ,
, , ,
:
:, ,
( ),,
,
)
, HOMO-LUMO- , , , ,
, , .
, , .
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
19 Structure-Activity(Property) Relationships
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 + k0C. Hansch, T. Fujita J.Am.Chem.Soc. 1964, 86, 1616;C. Hansch Acc. Chem. Res. 1969, 2, 232.
Anticonvulsant activity of 1,4-benzodiazepinones:
R
NH
N
Ph
O
(R = Cl, Br, CN, NO2, CF3, N(CH3)2, SCH3, SEt, n-BuS, SOCH3)
log(1/C) = 0.144 - 0.307 2 +1.291 + 4.558n=10, r=0.87, s=0.47
E.J.Lien, R.C.H.Liao, H.G.Shinouda J.Pharm.Sci. 1979,68, 463.
Additive schemes:A = Ai n (sum 1,2,. . . N) A = A0+ Ai n (sum 1,2,. . . N)
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
20 Structure-Activity(Property)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)
Antiadrenergic activity of substitutedN,N-dimethyl-a-bromophenylamines:
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
X
Y CHCH2N(CH3)2Br
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
21
( ) ( )
«…
».
Hermann L., 1868.
«…
,
».Brown A., 1868
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
22
Randic Index ( )
123
1 1
= 1/(3)1/2+1/(3)1/2+1/(6)1/2+1/(2)1/2=2.27
CH3
CH
CH3
CH2
CH3
C1 C2 C3 C4 C5
C1 1 0 0 0C2 1 1 0 1C3 0 1 1 0C4 0 0 1 0C5 0 1 0 0
C1
C2
C5
C3
C4
31
2 4
= ( i j)-1/2
bonds
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
23
Hologram QSAR
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
24 CoMFA
Comparative Molecular Field Analysis
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
25Clic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
26
» ; = nm
m1 m2 m3 …. mk ;k n; mi mj = 0; mi = ni ; ni = n
i : pi = ni/n:
I = - pi log2 pi
============================================================
INFORMATIO (Latina) – ", " ".,
.” / . /
.” / . / – .” / , . /
======================================================
MIN: M = m1 ; n = n1 ; p1 = 1 ; I = I` = 0:
MAX: ni = 1 ; pi = 1/n ; I = log2 n ; I` = n log2 n
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
24,2)81(812)41(413 lblbI bit
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
28
============================================================
, , . .
” ..
I = 0
..
I 0
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
29
.
I(A) = lb(N/1), I(B) = lb(N/8), I(C) = lb(N/16), I(D) = lb(N/24)N – .
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
30,
.
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
31,
.
Br
F
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
32
QSAR
1.
.
2. , -.
3.
.
4. QSAR-
.
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
33QSAR
.
1 2.2
2 3.0
3 4.1
… … …
N 0.5
O
O
S1 S2 S3 … SM
1.2 1.3
1.7 … 1.9
2.7 2.8
3.4 … 2.1
3.3 4.8
0.1 … -2.1
… … … … … …
1 2 8 … 10
O
O
QSAR
A = f (S1,S2,S3,…,SM)
.
.
..
1 2.1 2.5
2 3.2 2.6
3 4.0 4.2
… … … …
OH
Cl
O NH2
..
..
1 ? 2.6
2 ? 5.0
3 ? 6.0
… … … …
NH
NH NH
CH2
CH
O
NH2
O
NHNH2
O NH2
O
NH2
O
CH
DA?
”, “ ”
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
34Clic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
35
= f [mxk(i)]Ai^m ,
Ai^m
- i- ,
m- QSAR
mxk(i)
- k- i- m- QSAR
R2, Q2, R2test1 1
)Ai^mAi
^̂ =m=1
M
M
i=1,N; m=1,M
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
36 QSAR (Domain Applicability – DA)
*
**
** *
*
*
*
R
R= dav + 3*x
x
x
x
x
x
T1
T2
DA
DA
-- DA
T1, T2
- DA
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
37
4 D
3 D
2 D
1 D
-
1.4; 2.3; 3.1
1; 2; 3; 4
+; -
@; #; $; %
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
38(SiRMS)
: n!/4! /(n-4)!, n-
ClH
( )
• ………………………………..
• « »
• …………………..
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
39
CoMFAHASLGRID
CoMSiA
CODESSAEMMA
DRAGON HQSAR
2D-4D
3D2D NH2
OCH3
OH
3D
2D
NH2
OCH3
OH
2D - 4D
1 0 0 0
0 0 0 1
- ,.,.
.
1 0, 1 0 1
0 0 0, 1 1
1- , 0-
QSAR Clic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
40
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
CoMFA CoMSIA EVA HQSAR SiRMS(2D) SiRMS(3D)
R2
Q2
R2test
QSAR Sutherland J.J.; O’Brien L.A.; Weaver D.F. AComparison of Methods for Modeling QuantitativeStructure—Activity Relationships.J. Med. Chem. 2004, 47, 5541-5554CoMFA - Comparative Molecular Field AnalysisCoMSiA - Comparative Molecular Similarity IndicesAnalysisEVA - Eigenvalue AnalysisHQSAR - Holographic QSARCerius2 - QSAR software
Angiotensin ConvertingEnzyme (ACE) inhibitors
NH
N
O
R1R4
n
R2
R3 XY
– 76 – 38 .
R2-
Q2-
R2t-
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
41 QSAR
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
42
, %
NONH2
NH2
40 40 28
ON
ONCH3 CH3
CH3 O
15 14 8
CH3
O
OH
O
NNH
NH
O
-4 -15 -10
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
43
5-
E=2.1 kcal/mol,lgTID50=0.6
E=2.9 kcal/mol, lgTID50=1.1
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
44,
30%
30%
5%
10%
5%
20%
electrostatic
hydrophobic
H - bonding
dispersionic
other
individuality ofatoms
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
45 Combinational QSAR Modeling of ChemicalToxicants Tested Against Tetrahymena Pyriformis
Participants:UNC - University of North Carolina, Chapel Hill, NC, USALPU - Louis Pasteur University, Strasbourg, FranceUI - University of Insubria, Varese, ItalyUK - University of Kalmar, Kalmar, SwedenUBC - University of British Columbia,Vancouver, BC, CanadaVCCLAB - German Research Center for Environmental Health, Munich, GermanyPCI – A.V. Bogatsky Phys-Chem Institute NAS of Ukraine, Odessa, Ukraine
Training Set: 644compounds;Test Set 1: 339 compounds;Test Set 2: 110 compoundsUNC – Dragon, KNN;LPU – CODESSA, MLR;UI – Dragon, OLS;UK – Dragon, PLS;UBC – IND, SVM;VCCLAB – E-S+TI;ASSNPCI – SiRMS; PLS 0.5
0.55
0.6
0.65
0.7
0.75
0.8
0.85
0.9
UNC ULP UI UK VCCLAB UBC CONS PCI
R2t1R2t2
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
46
OCH3 O CH3
CH3
O
ONO
O
N
OCH3
N
NS
CH3
CH3
OCH3
O
S-7
NH2NH2
NH
NN
S
OH
PTU-23
NOH
N
NNH2
S OO
CH3 CH3
NN
N
O O
NH2
OHOH
OH
, in vitro 1 (
)
OH
N
N
HBB
L. Nikolaeva, A. S. Galabov.In vitro inhibitory effects ofdual combinations ofpicornavirus replicationinhibitors.// Acta virologica,1999
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
47
-1,5
-1
-0,5
0
0,5
1
1,5
2
2,5
3
-1,50 -1,00 -0,50 0,00 0,50 1,00 1,50 2,00 2,50 3,00
Obs
erve
d
Predicted
Antisynergism
Additivity
Synergism
Single
Developed Consensus QSAR ModelObserved vs predicted lgIC50 for external set
Models selected:472 SiRMS 2D PLS models
Work Set: 46 objects(8 drugs + 38 mixtures)
R2 > 0.89;Q2 > 0.86;A < 3
Y = lgIC50 of Poliovirus 1 Mahoney replication, µmolar
8 – fold external cross validation(every drug + all its mixtures out)
Consensus model:R2 = 0.94;S (ws) = 0.25;R2
test = 0.80;S (ts) = 0.45
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
48
NO
CH3N
NNH2
S OO
CH3 CH3
+
>NO
N
NNH2
S OO
CH3 CH3
+
NO
CH3N
NNH2 +
>NO
CH3N
OH
+
NO
N
NNH2 +
N
NS
CH3
CH3
O
N
N
+
NN
N
O
N
N+
>
>
>
>
>
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
49
PTU-23
PTU-23
1:1
1:1
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
50Clic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
51Clic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
52 :
-
............... .----
.
HIGH TROUGHPUTSCREENING
“HIT” “ LEAD”
”
--
…………………………………..
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
53
, -. ,
.
, ,
.
“This discipline concerns itself with the application of novel andnontrivial mathematics in a chemical context.”
Dennis Rouvray, Edithor of J.Math.Chem.
“ Mathematical Chemistry is a particular branch of theoretical chemistry with agreat deal of emphasis on topology, graph theory, group theory, and relatedsubject”. Löwdin P.-O.
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
5454
,,“high-throughput screening”
» (
),
, , .»
»
« »,
« » ( )
( )
«De novo»
QSAR
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
55
., ,
,,
, (“assembling”)
, , " G. N. Lewis
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
56
( , -.) :
Structure-based design
, :
de-novo design
,:
QSAR (Qualitative Structure-Activity Relationship)
:“ high throughput screening”
Click h
ere to
buy
ABB
YY PDF Transformer 2.0
www.ABBYY.comClic
k here
to buy
ABB
YY PDF Transformer 2.0
www.ABBYY.com
