Individual Hydrogen‐Bond Strength QSPR Modelling with ISIDA Local Descriptors: a Step Towards Polyfunctional Molecules

Here, we introduce new ISIDA fragment descriptors able to describe “local” properties related to selected atoms or molecular fragments. These descriptors have been applied for QSPR modelling of the H‐bond basicity scale pKBHX, measured by the 1 : 1 complexation constant of a series of organic acceptors (H‐bond bases) with 4‐fluorophenol as the reference H‐bond donor in CCl4 at 298 K. Unlike previous QSPR studies of H‐bond complexation, the models based on these new descriptors are able to predict the H‐bond basicity of different acceptor centres on the same polyfunctional molecule. QSPR models were obtained using support vector machine and ensemble multiple linear regression methods on a set of 537 organic compounds including 5 bifunctional molecules. They were validated with cross‐validation procedures and with two external test sets. The best model displays good predictive performance on a large test set of 451 mono‐ and bifunctional molecules: a root‐mean squared error RMSE=0.26 and a determination coefficient R2=0.91. It is implemented on our website (http://infochim.u‐strasbg.fr/webserv/VSEngine.html) together with the estimation of its applicability domain and an automatic detection of potential H‐bond acceptors.

[1]  M. Berthelot,et al.  The nicotinic pharmacophore: thermodynamics of the hydrogen-bonding complexation of nicotine, nornicotine, and models. , 2003, The Journal of organic chemistry.

[2]  R. Drago,et al.  Quantitative prediction and analysis of enthalpies for the interaction of gas-phase ion-ion, gas-phase ion-molecule, and molecule-molecule Lewis acid-base system , 1981 .

[3]  Alexandre Varnek,et al.  Substructural fragments: an universal language to encode reactions, molecular and supramolecular structures , 2005, J. Comput. Aided Mol. Des..

[4]  B. Wayland,et al.  A Double-Scale Equation for Correlating Enthalpies of Lewis Acid-Base Interactions , 1965 .

[5]  I. Tetko,et al.  ISIDA - Platform for Virtual Screening Based on Fragment and Pharmacophoric Descriptors , 2008 .

[6]  D. Horvath,et al.  ISIDA Property‐Labelled Fragment Descriptors , 2010, Molecular informatics.

[7]  Horvath Dragos,et al.  Predicting the predictability: a unified approach to the applicability domain problem of QSAR models. , 2009, Journal of chemical information and modeling.

[8]  M. Berthelot,et al.  Can semi-empirical calculations yield reasonable estimates of hydrogen-bonding basicity? The case of nitriles , 1997 .

[9]  Michael H. Abraham,et al.  Hydrogen bonding. Part 7. A scale of solute hydrogen-bond acidity based on log K values for complexation in tetrachloromethane , 1989 .

[10]  Igor V Tetko,et al.  Estimation of Acid Dissociation Constants Using Graph Kernels , 2010, Molecular informatics.

[11]  Michael H. Abraham,et al.  Hydrogen bonding. Part 9. Solute proton donor and proton acceptor scales for use in drug design , 1989 .

[12]  A. Sherry,et al.  Linear enthalpy-spectral shift correlations for 2,2,2-trifluoroethanol , 1970 .

[13]  G. Gilli,et al.  The Nature of the Hydrogen Bond , 2009 .

[14]  Michael H. Abraham,et al.  A general treatment of hydrogen bond complexation constants in tetrachloromethane , 1988 .

[15]  Timothy Clark,et al.  Economical and Accurate Protocol for Calculating Hydrogen-Bond-Acceptor Strengths , 2013, J. Chem. Inf. Model..

[16]  Hydrogen Bonding of Progesterone: a Combined Theoretical, Spectroscopic, Thermodynamic, and Crystallographic Database Study , 2000 .

[17]  P. Kollman,et al.  Nature of the hydrogen bond. Dimers involving electronegative atoms of the first row , 1971 .

[18]  Gerta Rücker,et al.  y-Randomization and Its Variants in QSPR/QSAR , 2007, J. Chem. Inf. Model..

[19]  Virginie B. Arnaud,et al.  Multiple Hydrogen-Bond Accepting Capacities of Polybasic Molecules: The Case of Cotinine , 2004 .

[20]  Peter Ertl,et al.  Estimation of pKa for Druglike Compounds Using Semiempirical and Information-Based Descriptors , 2007, J. Chem. Inf. Model..

[21]  M. Berthelot,et al.  The exceptional hydrogen-bond properties of neutral and protonated lobeline. , 2007, The journal of physical chemistry. A.

[22]  Peter A. Kollman,et al.  Theoretical studies of hydrogen-bonded dimers. Complexes involving HF, H2O, NH3, CH1, H2S, PH3, HCN, HNC, HCP, CH2NH, H2CS, H2CO, CH4, CF3,H, C2H2, C2H4, C6H6, F- and H3O+ , 1975 .

[23]  Timothy Clark,et al.  A QSPR-Approach to the Estimation of the pKHB of Six-Membered Nitrogen-Heterocycles using Quantum Mechanically Derived Descriptors , 2002, Journal of molecular modeling.

[24]  Virginie B. Arnaud,et al.  Hydrogen-Bond Accepting Strength of Five-Membered N-Heterocycles: The Case of Substituted Phenylpyrrolines and Myosmines , 2009 .

[25]  Igor V. Tetko,et al.  Exhaustive QSPR Studies of a Large Diverse Set of Ionic Liquids: How Accurately Can We Predict Melting Points? , 2007, J. Chem. Inf. Model..

[26]  Olivier Lamarche,et al.  Theoretical prediction of the hydrogen-bond basicity pK(HB). , 2002, Chemistry.

[27]  Oleg A. Raevsky,et al.  Complete Thermodynamic Description of H‐Bonding in the Framework of Multiplicative Approach , 1992 .

[28]  Chih-Jen Lin,et al.  LIBSVM: A library for support vector machines , 2011, TIST.

[29]  M. Berthelot,et al.  A theoretical evaluation of the pKHB and DeltaH[symbol: see text]HB hydrogen-bond scales of nitrogen bases. , 2008, Chemistry.

[30]  Aurélien Planchat,et al.  Structural features and hydrogen-bond properties of galanthamine and codeine: an experimental and theoretical study. , 2011, Chemistry.

[31]  O. A. Raevsky.  QUANTIFICATION OF NON-COVALENT INTERACTIONS ON THE BASIS OF THE THERMODYNAMIC HYDROGEN BOND PARAMETERS , 1997 .

[32]  Paul von Ragué Schleyer,et al.  Studies of hydrogen-bonded complex formation with p-fluorophenol. V. Linear free energy relationships with OH reference acids , 1969 .

[33]  A. Varnek,et al.  Structure—property modeling of metal binders using molecular fragments , 2004 .

[34]  Alexandre Varnek,et al.  Modeling of Ion Complexation and Extraction Using Substructural Molecular Fragments , 2000, J. Chem. Inf. Comput. Sci..

[35]  Thomas G. Dietterich.  Approximate Statistical Tests for Comparing Supervised Classification Learning Algorithms , 1998, Neural Computation.

[36]  S. Lifson,et al.  Energy functions for peptides and proteins. I. Derivation of a consistent force field including the hydrogen bond from amide crystals. , 1974, Journal of the American Chemical Society.

[37]  Viktorya Aviyente,et al.  Interpretation of hydrogen bonding in the weak and strong regions using conceptual DFT descriptors. , 2006, The journal of physical chemistry. A.

[38]  Paul L. A. Popelier,et al.  Theoretical Prediction of Hydrogen-Bond Basicity pKBHX Using Quantum Chemical Topology Descriptors , 2014, J. Chem. Inf. Model..

[39]  Alexandre Varnek,et al.  New Approach for Accurate QSPR Modeling of Metal Complexation: Application to Stability Constants of Complexes of Lanthanide Ions Ln 3+ , Ag + , Zn 2+ , Cd 2+ and Hg 2+ with Organic Ligands in Water , 2012 .

[40]  David J. Nesbitt,et al.  Defining the hydrogen bond: An account (IUPAC Technical Report) , 2011 .

[41]  Igor V. Tetko,et al.  Critical Assessment of QSAR Models of Environmental Toxicity against Tetrahymena pyriformis: Focusing on Applicability Domain and Overfitting by Variable Selection , 2008, J. Chem. Inf. Model..

[42]  Gastone Gilli,et al.  The Nature of the Hydrogen Bond: Outline of a Comprehensive Hydrogen Bond Theory , 2009 .

[43]  Christian Laurence,et al.  The pK(BHX) database: toward a better understanding of hydrogen-bond basicity for medicinal chemists. , 2009, Journal of medicinal chemistry.

[44]  David J. Nesbitt,et al.  Definition of the hydrogen bond (IUPAC Recommendations 2011) , 2011 .