1 Com putational Com putational Chem istry forCrop Chem istry forCrop Protection Research Protection Research Klaus-Jürgen Schleifer Com putationalChem istry & Biology BASF SE,Ludwigshafen 13.09.2008 Istanbul,SommerSchool,KJS 2 BASF –The Chem icalCom pany The world’s leading chem ical com pany O ffers intelligentsystem solutions and high-value products foralm ostall industries Sales 2007: €57,951 m illion Incom e from operations (EBIT)2007: €7,316 m illion Em ployees atyear-end2007:95,175 BASF ata Glance
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Com putational Com putational Chem istry for Crop Chem istry for Crop Protection ResearchProtection Research
Klaus-Jürgen Schleifer
Com putational Chem istry & Biology BASF SE, Ludw igshafen
13.09.2008 Istanbul, Som m erSchool, KJS 2
BASF – The Chem ical Com pany
The world’s leading chem ical com pany
O ffers intelligent system solutions and high-value products for alm ost all industries
Sales 2007: €57,951 m illion
Incom e from operations (EBIT) 2007: €7,316 m illion
Em ployeesat year-end 2007: 95,175
BASF at a Glance
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13.09.2008 Istanbul, Som m erSchool, KJS 3
BASF s Portfolio
Plastics
Perform anceProducts
AgriculturalSolutions
O il & G as
Chem icals
FunctionalSolutions
13.09.2008 Istanbul, Som m erSchool, KJS 4
Perform anceProducts
AgriculturalSolutions
Chem icals
Plastics
O il & G as
FunctionalSolutions
BASF s Portfolio
3
13.09.2008 Istanbul, Som m erSchool, KJS 5
Insecticidesagainstharm fulinsectpests
Herbicidesagainstw eeds
Fungicidesagainst harm ful
diseases
CropCrop protectionprotection
Otherse.g. grow th regulators
AgriculturalSolutions
13.09.2008 Istanbul, Som m erSchool, KJS 6
Negligible residues in food
Ecologically harm less
Excellentefficacy(betterthan currentm arket
standards)
Dem ands of a new Active Ingredient for Crop Protection
Active ingredientresearch forcropprotection is a m ultidim ensional task!
No adverse effects on w ild life
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HT-screening
com pound library
Active – but w hat is its m ode of action ?
Target activity – and in the greenhouse?
greenhouse-screening
optim isation
new lead-structures & developm ent products
hits
O rganism -based M echanism -based
How do w e find new Active Ingredients?
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Developm ent Candidate
1
Dossier
0 10
Lead Product
8
ProductDevelopm ent
Years2 3 4 5 6 7 9
LeadIdentification Registration
Research Developm ent
LeadOptim ization
R&D cost per product around $ 250 m illion (industry average)
R&D Process
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Developm ent Candidate
1
Dossier
0 10
Lead Product
8
ProductDevelopm ent
Years2 3 4 5 6 7 9
LeadIdentification Registration
LeadOptim ization
R&D cost per product around $ 250 m illion (industry average)
R&D Process
M olecularM odellingSupport
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Negligible residues in foodExcellentefficacy
(betterthan currentm arketstandards)
Issues addressed by M olecular M odelling and Chem oinform atics
Ecologically harm lessEcologically harm less No adverse effects on wild lifeNo adverse effects on wild life
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Issues addressed by M olecular M odelling and Chem oinform atics
Excellentefficacy(betterthan currentm arket
standards)
chem oinform atics toolsforphys-chempropertycalculationselection rulesforscreening librariesabsorption & distribution effects
m olecularm odelling m ethodsforactivitypredictionrationalise SARsynthesis priorisation
Ecologically harm lessEcologically harm less No adverse effects on wild lifeNo adverse effects on wild life
13.09.2008 Istanbul, Som m erSchool, KJS 12
Issues addressed by M olecular M odelling and Chem oinform atics
Excellentefficacy(betterthan currentm arket
standards)
chem oinform atics toolsforphys-chempropertycalculationselection rulesforscreening librariesabsorption & distribution effects
m olecularm odelling m ethods foractivity predictionrationalise SARsynthesis priorisation
Ecologically harm lessEcologically harm less No adverse effects on wild lifeNo adverse effects on wild life
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M olecularM odelling TechniquesTw o M ain Categories
Ligand-BasedDrug Design
Structure-BasedDrug Design
no protein 3D-structure,no active ligands
no protein 3D-structure,active ligands
protein 3D-structure, active ligands
protein 3D-structure, no active ligands
Perform experim ents De novo design
Docking & scoringFree-energy –calculation
Pharm acophores
3D-QSAR
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Ligand-BasedDrug Design
Structure-BasedDrug Design
no protein 3D-structure,no active ligands
no protein 3D-structure,active ligands
protein 3D-structure, active ligands
protein 3D-structure, no active ligands
Perform experim ents De novo design
Docking & scoringFree-energy –calculation
Pharm acophores
3D-QSAR
M olecularM odelling TechniquesTw o M ain Categories
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find the com m on features that are im portant in binding to the biologically relevant receptor (in the absence of structural inform ation about the receptor)
correlate 3D-structural properties with biologicalactivity
considered properties:
electrostatic
donor/acceptor
steric
hydrophobic
use the resulting m odelto predictthe activityof new analogues
3D-QSAR M odels:CoM SIA-M ethodology*
targetactivity(IC50-values)
*Klebe et al., J. M ed. Chem ., 1994, 37, p. 4130-4146
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Exam ple 1: Strobilurines -Fungicides from Fungi
Buchenschleim rübling(Oudem ansiella m ucida)
O
O
O
O
O udem ansin A
Defensive chem icals isolated from fungi
Kiefernzapfenrübling(Strobilurus tenacellus) Strobilurin A
OO
O
M ode of action
Strobilurinesblock the fungalenergyproduction byinhibitionof the com plexIII of therespiratorychain.
I
NADH
NAD+
Succinate
Fum arate
H+ H+
Cytb *
III
Cytc12e-IV
H2O
1/2 O 2
H+
UQpool
CytcATP
Synthase
H+ADP
ATP
III
NADH
NAD+
Succinate
Fum arate
H+ H+
Cytb *
III
Cytc12e-IV
H2O
1/2 O 2
H+
UQpool
CytcATP
Synthase
H+ADP
ATP
III
NADH
NAD+
Succinate
Fum arate
H+ H+
Cytb *
III
Cytc12e-IV
H2O
1/2 O 2
H+
UQpool
CytcATP
Synthase
H+ADP
ATP
II
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3D-Q SAR M odel forStrobilurines
Input: Chem ically diverse ligandsw ith different activity levels
3D-conform ationgeneration
structuralalignm ent
very high activity (IC50 < 10-9)high activity (IC50 < 10