Quantitative Structure-Activity Relationships Quantitative Structure-Property-Relationships QSAR & QSPR

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Quantitative Structure-Activity Relationships Quantitative Structure-Property-Relationships QSAR & QSPR. Alexandre Varnek Facult de Chimie, ULP, Strasbourg, FRANCE. History of QSAR. Dmitry Mendelev (1834 1907). Discoverer of the Periodic Table an early Chemoinformatician . - PowerPoint PPT Presentation

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Quantitative Structure-Activity Relationships Quantitative Structure-Property-Relationships QSAR & QSPR Alexandre VarnekFacult de Chimie, ULP, Strasbourg, FRANCEQuantitative Structure Activity Relationship (QSAR)Quantitative Structure Property Relationship (QSPR) History of QSARDmitry Mendelev (1834 1907)Russian chemist who arranged the 63 known elements into a periodic table based on atomic mass, which he published in Principles of Chemistry in 1869. Mendelev left space for new elements, and predicted three yet-to-be-discovered elements: Ga (1875), Sc (1879) and Ge (1886). Discoverer of the Periodic Table an early ChemoinformaticianPeriodic TableChemical properties of elements gradually vary along the two axisHistory of QSAR1868, D. Mendeleev The Periodic Table of Elements1868, A. Crum-Brown and T.R. Fraser formulated a suggestion that physiological activity of molecules depends on their constitution: Activity = F(structure) They studied a series of quaternized strychnine derivatives, some of which possess activity similar to curare in paralyzing muscle.1869, B.J. Richardson narcotic effect of primary alcohols varies in proportion to their molecular weights.History of QSAR1893, C. Richet has shown that toxicities of some simple organic compounds (ethers, alcohols, ketones) were inversely related to their solubility in water.1899, H. Meyer and 1901, E. Overton have found variation of the potencies of narcotic compounds with LogP. 1904, J. Traube found a linear relation between narcosis and surface tension. History of QSAR1937, L.P. Hammett studied chemical reactivity of substituted benzenes: Hammett equation, Linear Free Energy Relationship (LFER)1939, J. Fergusson formulated a concept linking narcotic activity, logP and thermodynamics.1952- 1956, R.W. Taft devised a procedure for separating polar, steric and resonance effects.History of QSAR1964, C. Hansch and T. Fujita: the biologists Hammett equation.1964, Free and Wilson, QSAR on fragments.1970s 1980s development of 2D QSAR (descriptors, mathematical formalism). 1980s 1990s, development of 3D QSAR (pharmacophores, CoMFA, docking). 1990s present, virtual screening.1934 - Hammett1934 - HammettssHere, the size of R affects the rate of reaction by blocking nucleophilic attack by water. Taft quantified the steric (spatial) effects using the hydrolysis of esters:In this case, the steric effects were quantified by the Taft parameter Es: k is the rate constant for ester hydrolysis. This expression is analogous to the Hammett equation. Steric effectsCompare some extreme values:Note: H is usually used as the reference substituent (Es(0)), but sometimes when another group, such as methyl (Me) is used as the reference, as in the chemical equation above, the value becomes 1.24. Es Values for Various SubstituentsHMePrt-BuFClBrOHSHNO2C6H5CNNH20.0-1.24-1.60-2.78-0.46-0.97-1.16-0.55-1.07-2.52-3.82-0.51-0.61Organophosphates must be hydrolysed to be active and it is observed that their biological activity is directly related to the Taft steric parameter ES for the substituent R by the equation:Es may be used in other chemical reactions and to explain biological activities, for example the hydrolysis of inhibitors of acetylcholine esterase. Steric effectsUsually, logP instead of P is usedlogP > 0, the compound prefers hydrophobic (unpolar) medialogP > 0, the compound prefers polar media Octanol/water partition coefficientBiological activity as a function of logPHansch AnalysisBiological Activity = log1/C C, drug concentration causes EC50, GI50, etc. EL (electronic descriptor): Hammett constant ( m, p, p0, p+, p-, R, F )HPh (hydrophobicity descriptor): hydrophobic subst. constant, log P octanol/water partition coeff. ST (steric descriptor): Taft steric constant Biological Activity = f (EL, ST, HPh) + constant Hansch, C.; Fujita, T. J. Am. Chem. Soc., 1964, 86, 1616. log1/C = a ( log P )2 + b log P + + Es + CPhysicochemical properties can be broadly classiied into three general types: Electronic Steric Hydrophobic Hansch AnalysisBiological Activity = f (Physicochemical properties ) + constant DescriptorsMolecular StructureACTIVITIESRepresentationFeature Selection & MappingDescriptorsQuantitative structure-activity relationships correlate, within congeneric series of compounds, their chemical or biological activities, either with certain structural features or with atomic, group or molecular descriptors.Quantitative Structure Activity Relationship (QSAR) Katiritzky, A. R. ; Lovanov, V. S.; Karelson, M. Chem. Soc. Rev. 1995, 24, 279-287 The molecular descriptor is the final result of a logic and mathematical procedure which transforms chemical information encoded within a symbolic representation of a molecule into a useful number or the result of some standardized experiment.Definition of molecular descriptorRoberto Todeschini and Viviana ConsonniA complete description of all the molecular descriptors is given in:Handbook of Molecular DescriptorsRoberto Todeschini and Viviana ConsonniWILEY - VCH, Mannheim, Germany - 2000Methods and Principles in Medicinal ChemistryVolume 11Edited by:H. KubinyiR. Mannholdxx. TimmermannDescriptors from Codessa ProTopologicalFragmentsReceptor surfaceStructuralInformation-contentSpatialElectronicThermodynamicConformationalQuantum mechanicalDescriptor FamiliesProducts Plus Molecular and Quantum MethodsDescriptors - calculable molecular attributes that govern particular macroscopic propertiesMolecular Descriptors 1D (atom counts, MW, number of functional groups, )2D (topological indices, BCUT, TPSA, Shannon enthropy, ) 3D (geometrical parameters, molecular surfaces, parameters calculated in quantum chemistry programs, ) Classification based on the dimensionality of structure presentationMolecular Descriptors 1DConstitutional descriptorsnumber of atoms absolute and relative numbers of C, H, O, S, N, F, Cl, Br, I, P atoms number of bonds (single, double, triple and aromatic bonds) number of benzene rings, number of benzene rings divided by the number of atoms molecular weight and average atomic weight Number of rotatable bonds (All terminal H atoms are ignored) Hbond acceptor - Number of hydrogen bond acceptors Hbond donor - Number of hydrogen bond donors These simple descriptors reflect only the molecular composition of the compound without using the geometry or electronic structure of the molecule.Molecular Descriptors 2DTopological DescriptorsDescriptors based on the molecular graph representation are widely used in QSPR, QSAR studies because they help to differentiate the molecules according mostly to their size, degree of branching, flexibility and overall shape.Total adjacency index: A = (1/2) For G1 and G2, A = 5.This TI can only distinguish between structures having different number of cycles (for cyclohexane A = 6).TI based on the adjacency matrixM1 = M2 = where the vertex degree di is a number of s bonds involving atom i excluding bonds to H atoms. TI based on the adjacency matrix : Zagreb group indices Zagreb group indices were introduced to characterize branching M1 = M2 = Zagreb group indices M1(G2) = 2*12 +4*22 = 18M1(G2) = 2*(1*2) +3*(2*2) = 16M1(G1) = 4*12 +2*32 = 22M2(G1) = 4*(1*3) +1*(3*3) = 21Randis molecular connectivity indexRandic introduced a connectivity index similar to M2R = M. Randi, J. Am. Chem. Soc., 97, 6609 (1975).The entry dij of the distance matrix indicates the number of edges in the shortest path between vertices i and j. The Wiener index (the first TI !) accounts for the branching: W(G1) = 29 W(G2) = 35 Reference: H. Wiener, J. Am. Chem. Soc., 69, 17 (1947)TI based on the Distance Matrix: the Wiener Index Peter Ertl, Bernhard Rohde, and Paul Selzer, J. Med. Chem. 2000, 43, 3714-3717TPSA - Topological Polar Surface AreaTPSA - Topological Polar Surface AreaTPSA - Topological Polar Surface Area3D PSA vs TPSA for 34 810 molecules from theWorld Drug IndexMoments of inertia - rigid rotator approximation - The moments of inertia characterize the mass distribution in the molecule. Geometrical descriptorsArea - Molecular surface area descriptor - Describes the van der Waals area of molecule - related to binding, transport, and solubility1. Rohrbaugh, R.H., Jurs, P.C., Anal.Chim. Acta, 1987. 199, 99-109.Shadow indices1 - Surface area projections Radius of gyration Molecular Descriptors 3DSteric parametersLength-to-breadth ratio : L/B 1 Molecular thickness Ovality 2 (ratio of the actual surface area and minimum surface )Molecular volume Sterimol parameters 3Taft steric parameter Es Janini, G.M.; Johnston, K.; Zielinski, W. L. Anal. Chem. 1975, 47, 670. Verloop, A.; Tipker, J. In Biological Activity and Chemical Structure, Buisman, J. A. K.(editors), Elsevier, Amsterdam, Netherlands, 1977, p63. Kourounakis, A.; Bodor, N. Pharm. Res. 1995, 12(8), 1199.Quantum Chemical DescriptorsQuantitative values calculated in QUANTUM MECHANICS (semi-empirical, HF Ab Initio or DFT ) calculations - Atomic charges (quant) - Atomic charges - LUMO - Lowest occupied molecular orbital energy HOMO - Highest occupied molecular orbital energy DIPOLE - Dipole moment - Components of dipole moment along inertia axes (Dx, Dy, Dz) Hf - Heat of formation Mean Polarizability - = 1/3(xx+yy+zz) EA Electron Affinity IP Ionization Potential E Energy of Protonation Electrostatic Potential - Lipophilic Descriptors (2D and 3D) Lipophilic Descriptors Octanol-water partition coefficient Hansch-Leo method (ClogP)Rekker's methodGhose-Grippen method(calculated logP based on summing contributions of atom types)logP(octanol-water), logP(alkane-water), logP(chloroform-water), logP(dichloroethane/water) Molecular lipophilicity potential (MLP)The MLP describe how lipophilicity is distributed all over the different parts of a molecule(lipophilicity maps and determination of hydro and lipophilic regions of a molecule) Lipophilic Descriptors Some LogPo/w Extremes in TherapyWhat do these Drugs have in Common?3D HydrophobicityAll molecules have the same logP ~1.5, but different 3D MLP pattern.hydrophobic hydrophilicDrug is exposed to a large varietyof pH values:Saliva pH 6.4Stomach pH 1.0 3.5Duodenum pH 5 7.5Jejunum pH 6.5 8 Colon pH 5.5 6.8Blood pH 7.4Liver-first-pass-effectwww.3dscience.com Example of oral administration:Lipophilic DescriptorsLog D Log PN : logP of the neutral form Log PI : logP of the ionized form logD The CalculationLogD may simply be calculated from predicted logP and pKa of the singly ionized species at certain pH:For acids:logD(pH) = logP log[1 + 10(pH - pKa)]For bases:logD(pH) = logP log[1 + 10(pKa - pH)]Fragment DescriptorsDescriptors: Cl, amide, COOH, Br, PhenylCl = 1amide = 1COOH = 1Br = 0Phenyl = 0I. SequencesII. Augmented AtomsISIDA Fragment descriptors Type of FragmentsI. SequencesII. Augmented AtomsType of FragmentsISIDA Fragment descriptors Etc.DataSetC-C-C-C-C-CC-C-C-N-C-CC=OC-C-C-NC-N-C-C*CISIDA FRAGMENTOR0 10 1 5 00 8 1 4 0 0 4 1 2 4the Pattern matrixCalculation of Descriptors+PATTERN MATRIXPROPERTY VALUES-0.2220.973-0.066Example : linear QSPR model PropertyPROPERTYcalc = -0.36 * NC-C-C-N-C-C + 0.27 * NC=O + 0.12 * NC-N-C*C + SoftwareDRAGONThe software DRAGON calculates 1664 molecular descriptors divided in 20 blocksCODESSA Pro calculate a large variety of molecular descriptors on the basis of the 3D geometrical structure and/or quantum-chemical parameters; develop (multi)linear and non-linear QSPRISIDA program calculates fragment descriptors; develop (multi)linear and non-linear QSPR models********************************************Just in case Measured LogP oct/wat is the same, 1.97*************

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