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ChemDiv
Agrochemistry Issue
Yury Putsykin Prof., D.Sc., The Director of Agrosintez; the core scientist in
Agrochemistry in CDRI, [email protected]
Yan Ivanenkov, Ph.D., The Head of
Computational Medicinal Chemistry Dept. ChemDiv, [email protected]
December 2013
The Spectrum of Computational Tools for VS routinely applied in ChemDiv
Also:
SPE,
MDS,
etc.
Our Experience in Computational Chemistry
Representative
examples of books
dedicated to
computational
chemistry with
chapters by ChemDiv
scientists
The Smart Mining
Software developed in
ChemDiv for virtual
screening and QSAR
analysis
More than 120 scientific
publications in the field of
modern computational
chemistry and QSAR
modeling, including
comprehensive reviews
and focused full-text
articles
ChemoSoftTM (CDRI)
Smart Mining (CDRI)
MolSoft ICM (MolSoft LLC)
Cerius2 (Accelrys)
Discovery Studio (Accelrys)
NeuroSolution (NeuroDimension)
ISIS Base (MDL)
AutoDock (Scripps)
Surflex (Biopharmics)
PyMOL (Biopharmics)
MOE (Molecular operating environment)
etc.
Software in ChemDiv
Substructure and Similarity Search Bioisosteric Morphing
Example: Morphing of
Quinazoline-like privileged
structures
Balakin K.V., Ivanenkov Y.A., et al.
Bioisosteric morphing in primary hit
optimization. Chem. Today, 2004,
22, 15-18.
Structure mining tools
Focused Agrochemistry
the reference database of more than 3K small-molecule compounds – known agrochemical agents;
► specific computational models successfully validated for the assessment of agrochemical activity and specificity (Kohonen- and Sammon-based mapping, Neural-nets (NN), recursive partitioning (RP), etc.);
► thematic library of more than 130 templates for synthesis with promising agrochemical activity (whole ChemDiv stock includes more than 1.5 mil.compounds with high diversity);
► ALS-, ACS and ACCase-specific models (3D-molecular docking approach & 3D-pharmacophore model) for the design of novel small-molecule ligands
We have:
► synthesis of novel organic compounds comprehensively covered by our computational background and expert opinion;
► the related biological evaluation of compounds for agrochemical activity;
► development of novel structures with high IP potential;
We can do:
The Main Focus is:
► considering agricultural ecology, select small-molecule compounds without a potentially
toxic points, e.g. Cl, Br, I, P, etc.;
► searching for new antidotes (ppp) against herbicides – a new route to expand the field of
known herbicide utilization – targeting new agricultures and weeds. As a good example -
mefenpyr-diethyl, an antidote against fenoxaprop-ethyl (Puma compositions) as well as
against Iodosulfuron (Sekator), / high selectivity and low phytotoxicity;
► with regard to fungicides, ppp could also be effectively used
for the reduction of a retardant effect;
► the privileged structures include: “amino acid” function mimetics, C-2 and C-3 amino
alcohols, diamines as well as glycols, compounds with F and CF3. etc.;
► the related biological screening for ppp activity can be properly performed in Agrosintez
mefenpyr-diethyl
Examples of Novel Agrochemicals Registered in 2011-2012
Colecalciferol
rodenticide
Oxathiapiprolin
fungicide
Pyrisoxazole
fungicide
Isofetamid
fungicide Pyflubumide
acaricide
Tolprocarbe
fungicideBenzovindiflupyr
fungicide
Flometoquin
insecticide
Flupyradifurone
insecticide
agro type compounds
insecticide 648
fungicide 326
herbicide 576
total 1550
descriptor definition
RotB no. of rotatable bonds
H_acceptor no. of H-bond acceptors
H_donor no. of H-bond donors
Log_Dlog of 1-octanol/water
partition coeff. at pH 7.4
insecticide fungicide herbicide
insecticide (in %, diff. 3D)
Similar models have also been developed based on Sammon algorithm,
RP as well as NN-based approach
the average percentage of correct classification - 80%
Kohonen-based model
Ref.dataset Molecular descriptors
(3D representation)
Differences in the distribution of
molecular descriptor values
HERBICIDES
ACCase inhibitors
ALS inhibitors
Auxin mimetics
Elongases inhibitors
GGPP cyclase inhibitors
PPO inhibitors
4-HPPD inhibitors
Weed cell cycle inhibitors
PDS inhibitors
EPSPS inhibitors
Photosystem I/II inhibitors
Inhibition of carotenoid
biosynthesis
DOXP synthase inhibitors
Glutamine synthetase inhibitors
DHP synthase inhibitors
Inhibition of cell wall
synthesis
Uncoupling
(membrane disruption)
Inhibition of lipid synthesis
(not ACCase inhibition)
Inhibition of auxin transport
Prominent Biotargets for Herbicides
ACS inhibitors
GST stimulators
14-reductase inhibitors
Examples of active compounds
ACCase inhibitors ALS inhibitors Auxin mimetics
pinoxaden
haloxyfop-R-methyl
fluazifop-P-butyl
chlorsulfuron
imazaquin
flumetsulam
triasulfuron
dicamba
clopyralid
2,4-D
aminopyralid
O
O
SO2CH
3
Cl
N
O
O CHCL2
CH3
ON
COOC2H
5
O
N
O
SO2CH
3
CF3
N
O
O CH3
CH3
Cl
NN
COOC2H
5
CH3
Cl
ClO
C2H
5O
N
CH3
CH3
O
O
Cl
N N
Cl
NO
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
O
O N
CH3
CH3 S
N
N O
N CH3
Cl
CH3
OO
O
O
O CH3 O
NO
CH3
O
O
N
N
N
O
CH3
CH3
CH3
N
N
O N
S
CH3CH
3Cl
N
N
N
O
N
N
O
O
OF
2C
N
CN
S
NN
O NF
ClS
OO CH
3
S
NN
CF3
O
N
O
F
CH3
CH3
NCl
O O
CH3
N
Cl
Cl
O
F
NO
N
O
O
aviglycine
benzobicyclone
benzocsakor isoxaflutole
cloquintocet-methyl
mefenpir-diethyl
petoksamid pyrimidifene
spiroksamin tiadinil trineksapak-ethylfamoksadon
fenazaquinefenamidone fentrazamid
fludioksonil
fluthiacet methyle
flufenacet
quinmerak
kvinoksifen
?
Examples of active compounds
Representative Examples of Synthetic Agro-templates
Suggested in ChemDiv Lib.
N
NN
O
O
R2a
R1a N
N
N
NR
1a
R2a
N
N
N
O
R2a
R1a
N
N
N
OR
1a
R2a R
2b
N
N
ON
R2a
R1a
N N
N
N N
OR
2a
R1a
R1b
N
ON
S
O
O
R2a
R1a
NN
O
N
O
R2a
R1a
R2b
NN
N
R3a
R2a
R1a
N
N O
O
R2a
R1a
R2b
N
N
NN
R2a
R1a
R1b N
O
OR
1a
R2a
N
N
NO
O
R2a
R1a
O
N
R3a
R2a
R1a
N
N
N
NR1a
R2a
N
N N
N
O
R3a
R1a
R2a
NN
S
N
N
R1a
R2a
R3a
NS
N
O
O
O
N
R3a
R2a
R2b
R1a N
N
O
R3a
R1a
R2a
N N
NN
N
R2a
R1a
R1b
N N
O
O
R2a
R1a
N
N
N
O
R3a
R1a
R2a
N
N
N O
R1a
R2a
N
N
OR1a
R1b
R2a
CM1218 CM1886CM2434_1 CM3189
CM2890 CL9652a
CM0221 CL3311
CM1042
CM1854
CM2889 CM3034
CL5373 CM2967 CM3476CL6963
CL5918 CM1062 CM0469a CM3137
CM1434
CL9209c
CM2600
CM2992
thiamine pyrophosphate = ThDP
ALS
O
O
O
CH3
N
N
N
S O
P OO
O
P
O
O
ONH
2
CH3
CH3
OHCH
3
OH
O
O
R
2-ketoacids
acetohydroxy acids
-CO2
OH
O
O
R
O
CH3
OH
O
OH
R
O
CH3
pyruvate
(pyruvate, 2-ketobutyrate)
2-acetolactate 2-aceto-2-hydroxybutyrate
valine and leucine isoleucine
BCCA
Mg2+ThDP anchoring
transition state
Glu579
Asp550
Asn577
ALS
ThDP
N
N
NH
N O
O
OH
OHOH
O
PO O
OP
O
O
O O
OH OH
N
N
N
N
NH2
Presumably, FAD plays a purely structural role, but it can undergo reduction toFADH2 as a side reaction of the catalytic cycle. Several sulfonylureas make
contacts with the isoalloxazine ring, but in many cases these contacts are notrequired for sufficient binding.
FAD
ThDP fragmentation occures
(carbanion formation)
blocked by Sulphonylureas further methabolism
A brief Insight into ALS mechanism of action
Chlorsulfuron in the active binding sites of АLS (А); a detailed site
composition and crucial binding points (B) / crystallographic data
(A) (B)
McCourt JA, Pang SS, Guddat LW, Duggleby RG. Elucidating the specificity of binding of sulfonylurea
herbicides to acetohydroxyacid synthase. Biochemistry. 2005, 44, 2330-8.
Conservative ALS binding site
Metsulfuron methyl Sulfometuron methyl
Tribenuron methyl
3D-overlapping
Examples of related sulphonylureas
Imazaquin and Chlorimuron ethyl in the
ABS of ALS
(crystallographic data)
the inhibition constants for yeast ALS range from 3.25 nM for Chlorimuron ethyl to 127 nM for
Chlorsulfuron
►the effect of active site tunnel mutations varies widely between these inhibitors. Thus, the G116S
mutation in yeast ALS increases the inhibition constant for Chlorimuron ethyl by more than 1000-
fold, while that for Chlorsulfuron is increased by less than 5-fold. These observations suggest that
the interactions with the protein must differ among various sulfonylureas
N
OH
O
N
NO
McCourt JA, Pang SS, King-Scott J, Guddat LW, Duggleby RG. Herbicide-binding sites revealed in the structure
of plant acetohydroxyacid synthase. Proc. Natl. Acad. Sci., 2006, 103(3), 569-73.
Examples of novel ALS-targeted privileged
scaffolds designed in silico
N NH
[O,S]
R1
D
S
O
O
O
R2
R1, preferably:
N
N
*
OAlk
OAlk
N
N
N
*
OAlk
OAlk
D = H, alkyl, alkenyl, etc.
Alk = Me, Et
[C,N]
N
[C,N]
N
N
NHO
S Ar/HetO
OR1
R2
R1, R2: preferably OAlk, Alk, Hal
N
NNX
X
OAlk
R
R
R
R1 = H, Alk, OAlk, Hal
Alk = Me, Et, X = C,N
SNH
O O
OAr/Het
*
1
2
3
R2 = *NH
SO O
O Ar/Het
R3 = OAlk (if X=C)
R1 = preferably OAlk, Alk
R2 = H, Alk
N
NN
[C,N]N
R
R
R
SNH
O O
Ar/Het*
NH
SAr/Het
O O
*
1
2
3
R3 =
[C,N] N
N NH
O O O
NS
AA
R
O
O
Alk
Alk
Ar/Het
R = OAlk, SO2R, COOR, CONR2, Hal, CF3, etc.
[C,N] N
N NH
O O O
NS
R
O
O
Alk
Alk
AAr/Het
R R
12
3
4
5
A brief Insight into ACCase mechanism of action
biotin
S
NH NH
O
(CH2)4
O
NH
(CH2)4
ACCase
lysine res.
OH O
O
PO
ADP O
OO
O OH
OP
O
O
O
bicarbonate
carbonyl-phosohate..
S
NNH
O
*
O
O
S
O
CoAH
HH
S
O
CoAOH
O
- ADP
malonyl-CoA
acetyl-CoA
Mg2+
Mg2+
ACCase
Glu296
Arg338
Arg292
Glu211
deprotonationof bicarbonate
nucleophile attack
CO2 and PO43-
release
Arg338
PO43- deprotonates biotin
carboxybiotin translocates to the carboxytransferase active site
S
O
CoAH
H -H
-transition state
- provides the malonyl-CoA substrate for the biosynthesis of flavonoids, LCFAs and their elongation
- inhibits carnitine transferase-I thereby blocking the transfer of FAs into the mitochondria
ACCase
BCCP
haloxyfop and
tepraloxydim block thecatalysis by competingwith the acetyl-CoA
CP-640186 competswith carboxybiotinN O
N
O N
O
The binding mode of pinoxaden
the electron density
at 2.8-A resolution the binding site for
pinoxaden
key interactions within
the binding site
overlay of the binding modes of
pinoxaden and tepraloxydim
overlay of the binding
modes of pinoxaden and
haloxyfop
Yu LP, Kim YS, Tong L. Mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A
carboxylase by pinoxaden. Proc. Natl. Acad. Sci. USA. 2010, 107(51), 22072-7.
orange – crystallographic data
yellow – docking results (E=-60 kcal/mol )
GOOD alignment
Pinoxaden in the active binding site
of ACCase (RSA data)
3D ACCase Docking Model
Tepraloxydim in the active
binding site of ACCase (RSA
data)
orange – crystallographic data
yellow – docking results (E=-54 kcal/mol )
GOOD alignment
NO O
CL2489 E=-60 kcal/mol
O O
N
Cl5932 E=-52 kcal/mol
NN
O
ON
O
F
F
CL3345 E=-66 kcal/mol
Examples of compounds with promising activity against ACCase
HIGH SCORE
HIGH SCORE
MODERATE SCORE
3D ACS Docking Model
Inhibitors of transient state
NO
N
O
O
aviglycine
orange – crystallographic data
yellow – docking results (E=~34 kcal/mol )
GOOD alignment
key Aas:
R407
E47
R150
Y19
Examples of compounds with promising activity against ACS
S
NO
O
N
O
O
N
CL1161 E=-56 kcal/mol
S
NO
O
N
O O
N
CL1161-1 E=-45 kcal/mol
NN
O
O
N
CL6690 E=-45 kcal/mol
CL3537 E=-50 kcal/mol
N
N
O
O
O
N
O
O
N
O
O
R1a
insecticide
ENT8184
CL0798
N
O
O
NN
NN
S
R2a R
1a
N
N
O
O
R2a
R1a
R1b
N
N
N
N
SR2a R
1a
ENT8184
affects cell division andcell elongation, auxin
PGR
CL3245CL6690
CL3318
N
O
O
ON
O
ON
N
O R2a
R1a
promotes pollination
PGRCL7718a
N
O
NO
NO
N O
N
R2a
R1a
NO
N O
N
R2a
R1a
fungicide
ICIA0858
CM0324CM0325
Examples of isosteric and topological analogues among
ChemDiv Argo-templates
ON
N
O
FF
F
N O
N
O
N
R2a
R1aR
1b
N O
N
O
N
R2a
R1a R
1b
N O
N
N
N
O
R1a
R2a
R1b
N
O
N
NR
2a
R1a
R1b
O
N
N O
N
R2a
R1a
R1b
N
O
N
N
N
O
R2aR
2b
R1a
N
N N
O
N
R1a
R1b
R2a R
2b
NN
O
ON
N
OR2a
R1a
herbicide
flufenican
CM0326
CM0327
CL2832
CM1866
CM0328
CM0183
CM1149d
CL7719a
NCl
O O
S
N
O O
N
N
O
R2a
R1a
R1b
S
N
OO
N
N
O
R1a
R1b
O
N
O
S
O
O
F
F
FO
N
F F
F
SO
O
N
R2a
R1a
R2b
N N
O
ON
N
O R2a
R1a
quinmerac
CL348CL348
CL948
isoxaflutol
CL7719
N
O
O
Cl
Cl
S
N
N
O
R3a R
3b
R1a
R2aN O
N
NO
O
R2a
R2b
R1a
N
N
O
O
N
O
R3a
R1a
R3b
R2a
N
ON O
R3a
R1a
R2a
NN
O
O
N
O
R3a R
2a
R1a
R1b
N
O
ON
N
O R2a
R1a
ррр antidotCL3410
CM1998
CL6788
CL9024
CL2582
CL7718a
acyclic analogues
invert analogues isosteric morphing
spiro-analogues
"next-in-class"
benoxacor
NH
O
NH
O
O
H
H
H
N
N
O
O
O
R2a
R1a
R1b
SNH
O
O
N
O
R3a
R2aR
1a
R1b
NH
O
O
N
R2aR
1a
R1b
N
O
N
N N
O
R1a
R2a
R1b
H
H
NN
O
O
R2a
R1aR
1b
H
H
N
N
O
O
R1a
R2a
H
SNH
O
O
N
O
R3a
R1a
R1b
O
ррр aviglycine
"pro-drug" moieties
H, alkyl
H, alkyl
"pro-drug" moieties
H, alkyl
alkyl
CL1161
H, alkyl
"pro-drug" moieties
CL2593
H, alkyl
CL2832
H, alkyl
CL6690
H, alkylCL2049
N-O
C(O)alkyl
N
N
Cl
Cl
O
OO
O
NS
O
R3a
NO
R2a
R1a
N
N
SO
O
OO
R3a
R3b
R1a
R2a
N N
O
N
N
R1a
R1b
N
N
N
O
N
O
R2a
R1a
R2b
R1b
R1c
R1d
R1e
NN
N
N
N
O
O
R3a
R2a
R1a
H
S
NN
O
O
N
O
R3a
R2a
R3b
R1a
R2b
R1b
R2c
R2d
R2e
S
ON
FF
F
S
O
O
NR
1a
R1b
H, Alkyl
CL5389
CL6065
CL6292
CL6441CL6527
CL7169
mefenpyr-diethyl
Me
Me
Me
O
O N
MeMe
O
N
N
O
SO
O
R2a
R1a
NO
N
O
O
O
R1a
R2a
R1b
N
O
N
R2a
R1a
R1b
O
N
R3a
R2a
R1a
N
N
R2a
R1aR
1b
N
N
N
O
R3a
R2a
R1a
R1bN
N
O
N
R2a
R1a
N
O
OR
1a
R2a
CL5116
CL3586b
CM2348
CM2967
CM1631
CM2368
CM1591
CM3034spiroksamin
O
N N
OO
ON
NOO
N
R2a
R2b
R1a
R1b
NO O
R1a
R1b R
1c
R1d
R1e
N
N
O O
R2a
R2b
R1a R
1b
R1c
R1dR
1e
O O
N
R1a
R1b
R1c
R2a
R1d
R2b
R1e
N
N
O O
N
OR
3a
R3b
R2aR
2b
R1a
R2cR
2d
R2e
S
N S
OO
O
O
N
O
R3a
R2a
R3b
R1a
R3c
R2b
R3d
CL9872
CL2489
CL2165
Cl5932
CL3345
CL7984
Pinoxaden
orange – Pinoxaden
yellow – CL2489
orange – Pinoxaden
yellow – 3345
Summary
► comprehensive in silico design of novel compounds using a range of
modern computational approaches including 3D-molecular docking,
Neural-Net modeling and 3D-pharmacophore searching;
► solid-phase as well as liquid-phase synthesis of novel compounds with
high diversity in structure using a variety of traditional and combinatorial
schemes;
► targeted library of small-molecule compounds ranged within 133
promising agrochemical templates selected in ChemDiv;
► analysis of patent landscape resulting in compounds with high IP
► HTS evaluation of novel compounds for agrochemical potency.
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