Recent Advances in QSAR Studies: Methods and Applications (Challenges and Advances in Computational Chemistry and Physics, 8)

Since the inception of this volume, the world s nancial climate has radically changed. Theemphasishasshiftedfromboomingeconomiesandeconomicgrowth totherealityofrecessionanddiminishingoutlook. Witheconomicdownturncomes opportunity, inallareasofchemistryfromresearchanddevelopmentthroughto productregistrationandriskassessment, replacementsarebeingsoughtforcostly time-consumingprocesses. Leadingamongstthereplacementsaremodelswithtrue predictivecapability. Ofthesecomputationalmodelsarepreferred. This volume addresses a broad need within various areas of the chemical industries, from pharmaceuticals and pesticides to personal products to provide computationalmethodstopredicttheeffects, activitiesandpropertiesofmolecules. Itaddressestheuseofmodelstodesignnewmoleculesandassesstheirfateand effectsbothtotheenvironmentandtohumanhealth. Thereisanemphasisrunning throughoutthisvolumetoproducerobustmodelssuitableforpurpose. Thevolume aimstoallowthereaderto nddataanddescriptorsanddevelop, discoverandutilise validmodels. Gdansk, Poland TomaszPuzyn Jackson, MS, USA JerzyLeszczynski Liverpool, UK MarkT. D. Cronin May2009 CONTENTS Part I Theory of QSAR 1 QuantitativeStructure ActivityRelationships(QSARs) ApplicationsandMethodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Mark T. D. Cronin 1. 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1. 2. PurposeofQSAR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1. 3. ApplicationsofQSAR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1. 4. Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1. 5. TheCornerstonesofSuccessfulPredictiveModels . . . . . . . . . . . . 7 1. 6. AValidated(Q)SARoraValidPrediction? . . . . . . . . . . . . . . . . . . 9 1. 7. UsinginSilicoTechniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1. 8. NewAreasforinSilicoModels. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 1. 9. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2 TheUseofQuantumMechanicsDerivedDescriptorsin ComputationalToxicology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Steven J. Enoch 2. 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 2. 2. TheSchrodingerEquation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 2. 3. Hartree FockTheory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2. 4. Semi-EmpiricalMethods: AM1andRM1. . . . . . . . . . . . . . . . . . . . 18 2. 5. ABInitio: DensityFunctionalTheory. . . . . . . . . . . . . . . . . . . . . . . 19 2. 6. QSARforNon-ReactiveMechanismsofAcute(Aquatic) Toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2. 7. QSARsforReactiveToxicityMechanisms. . . . . . . . . . . . . . . . . . . 21 2. 7. 1. AquaticToxicityandSkinSensitisation. . . . . . . . . . . . . 21 2. 7. 2. QSARsforMutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . 24 2. 8. FutureDirectionsandOutlook. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2. 9. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 vii viii Contents 3 MolecularDescriptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Viviana Consonni and Roberto Todeschini 3. 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3. 1. 1. De nitions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3. 1. 2. History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 3. 1. 3. Theoreticalvs. ExperimentalDescriptors. . . . . . . . . . . . 33 3. 2. MolecularRepresentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 3. 3. TopologicalIndexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 3. 3. 1. MolecularGraphs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 3. 3. 2. De nitionandCalculationofTopologicalIndexes(TIs) 39 3. 3. 3. Graph-TheoreticalMatrixes. . . . . . . . . . . . . . . . . . . . . . . 42 3. 3. 4. ConnectivityIndexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 3. 3. 5. CharacteristicPolynomial . . . . . . . . . . . . . . . . . . . . . . . . 50 3. 3. 6. SpectralIndexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 3. 4. AutocorrelationDescriptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ." Read more