BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
QxPR methods in biomedicine – effect of geometry optimization
Åsmund Rinnan
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
QSxR?! QSAR?? QSPR!?
• Quantitative• Structure• Activity or
Property• Relationship
Estrogen -receptor
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Basics of QSxR
2D 3D
O
OHO
OH
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Basic of QSxR3D Descriptors
MW: 270.241Dipole: 3.44SASA: 470.87FISA: 182.33PISA: 288.54Volume: 795.13DonorHB: 2AccptHB: 3.75Dip^2/V: 0.0149Ac*DN^.5/SA: 0.0113
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Basic of QSxR3D Descriptors
MW: 270.241Dipole: 3.44SASA: 470.87FISA: 182.33PISA: 288.54Volume: 795.13DonorHB: 2AccptHB: 3.75Dip^2/V: 0.0149Ac*DN^.5/SA: 0.0113
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Basics of QSxRDescriptors PLS
B
And the rest is chemometrics…
Attributeof interest
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Geometry optimizationBasics
O
OHO
OH
days
sec
min
h
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Accuracy vs. Time
UFF
AM1
PM3 HF
B3LYP
Mechanical Semi-empiricalDensity
FunctionalTheorem
Time consumption
Seconds Days
Theoretical level
IntroductionQuestionStudyResultsSummary
MM3*
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Accuracy vs. Time
UFF
AM1
PM3 HF
B3LYP
Mechanical Semi-empiricalDensity
FunctionalTheorem
Time consumption
Seconds Days
Theoretical level
IntroductionQuestionStudyResultsSummary
MM3*
1 80Dielectric constant
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Accuracy vs. Time
UFF
AM1
PM3 HF
Mechanical Semi-empiricalDensity
FunctionalTheorem
Time consumption
Seconds Days
Theoretical level
IntroductionQuestionStudyResultsSummary
MM3*
6-31g(d,p)
Basis setsSTO-3g
6-31gB3LYP
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
DataDatasets
O
OHO
OH
IsoflavonoidsOH
Aglycons
Estrogen like
compounds
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
O
O
OH
Isoflavonoids
Estrogen like
compounds
DataProperties
Melting point
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
DataProperties
OHAglycons
log P
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
DataOverview
UFF
AM1
PM3
HF
B3LYP
MM3*
Meltin
g p
oin
tlo
g P
x 2
x 3
x 3
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
DataDescriptors
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
MethodsValidation
Leave-one out cross-validation
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
MethodsVariable selection
Variable selection:• Jack-knifing• Principal variables
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
ResultsDescriptor package
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
ResultsDistance to optimal
Aglycons
Estrogen-like Isoflavonoids
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
ResultsPrediction qualityAglycons
Estrogen-like Isoflavonoids
BEST - BYG EN SUND TILVÆRELSE QSAR & CHEMOMETRICSÅsmund Rinnan
Royal Veterinary and Agricultural UniversityDenmark
Conclusion
UFF
AM1
PM3 HF
B3LYP
Mechanical Semi-empiricalDensity
FunctionalTheorem
Time consumption
Seconds Days
Theoretical level
MM3*