How to build a better molecule - NEQUIMED/IQSC/USP
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3/29/17 1 How to build a better molecule Imagine: 1. There seems to be a relationship between number of carbon atoms in a molecule and its melting point. 2. A simple mathematical model could be: M = kN + c Where k=slope and c = intercept 3. What values of k and c give the smallest error between the calculated melting points and the real ones? 4. Calculate by LINEAR REGRESSION 5. Now can be applied to predict the melting point of a new molecule. Machine learning Number of carbon atoms (N) Melting point (M) Process: 1. DESIGN a model 2. TRAIN the model 3. TEST the model k c
Transcript of How to build a better molecule - NEQUIMED/IQSC/USP
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Howtobuildabettermolecule
Imagine:
1. Thereseemstobearelationshipbetweennumberofcarbonatomsinamoleculeanditsmeltingpoint.
2. Asimplemathematicalmodelcouldbe:M=kN +cWherek=slopeandc=intercept
3. Whatvaluesofkandcgivethesmallesterrorbetweenthecalculatedmeltingpointsandtherealones?
4. CalculatebyLINEARREGRESSION
5. Nowcanbeappliedtopredictthemeltingpointofanewmolecule.
Machinelearning
Numberofcarbonatoms(N)
Meltin
gpo
int(M)
Process:1. DESIGNamodel2. TRAINthemodel3. TESTthemodel
k
c
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Similarly:
Biologicalactivity=f(propertiesofthemolecule)
Biologicalactivity=k1*descriptor1+k2*descriptor2+k3*descriptor3….+const.
QuantitativeStructure-ActivityRelationships
Descriptors:Variouspropertiesofthemolecule:• Lipophilicity• NumberofH-bonddonors• Molecularweight• Electronicparametersofsubstituents• Etc…
1. ConstructaQSARmodelusingchosendescriptors2. Optimise parameters(k1,k2,etc.)byMLR (orsimilar)onthetrainingset3. Checkperformanceusingaseparatetestset.
0-Ddescriptors:o Molecularweighto LogP
1-Ddescriptors:o Fingerprints
2-Ddescriptors:o Graph-related(numberofrings,numberofrotatablebonds)
3-Ddescriptors:o Sizeo Shapeo Surfacearea
Substituentdescriptors:o ElectronegativityofsubstituentX
QSAR:Moreondescriptors
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Free-WilsonAnalysis
FreeandWilson:substituenteffectsontheactivityofaclassofmolecules
Free-WilsonAnalysis
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3D-QSAR(CoMFA,CoMSIA)
Ateverygridpoint,calculatethesteric andelectrostatic energybetweenthemoleculeandaprobeatom(e.g.aCH3 carbocation)
3D-QSAR(CoMFA,CoMSIA)
(abitlikeFree-Wilsonanalysis)
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3D-QSAR(CoMFA,CoMSIA)
Choietal.,Bioorganic&MedicinalChemistryLetters,(2013),23,4540-4546
QSAR:Summary
1. QSARandrelatedmethodsaimtoextractthemaximumamountofinformationfromthedataavailable.• Themoredatayouhave,themorelikelyyouwillgetusefulinformation.
2. QSARmethodsrelyonamodel – thatthereissomeconsistentrelationshipbetweenthemeasured/predictedcharacteristicsofthemoleculesandtheiractivitythatcanbeexpressedmathematically.• Doyouknowallthemoleculeshavethesamemechanismofaction?
3. Modelvalidationdependsonasoundstatisticalanalysisofperformance,andwell-balancedtrainingandtestdatasets.• Hasthemodelbeentestedagainstatrulyindependentdataset?
