Theoretical Prediction of Hydrogen-Bond Basicity pKBHX Using Quantum Chemical Topology Descriptors

Hydrogen bonding plays an important role in the interaction of biological molecules and their local environment. Hydrogen-bond strengths have been described in terms of basicities by several different scales. The pKBHX scale has been developed with the interests of medicinal chemists in mind. The scale uses equilibrium constants of acid···base complexes to describe basicity and is therefore linked to Gibbs free energy. Site specific data for polyfunctional bases are also available. The pKBHX scale applies to all hydrogen-bond donors (HBDs) where the HBD functional group is either OH, NH, or NH+. It has been found that pKBHX can be described in terms of a descriptor defined by quantum chemical topology, ΔE(H), which is the change in atomic energy of the hydrogen atom upon complexation. Essentially the computed energy of the HBD hydrogen atom correlates with a set of 41 HBAs for five common HBDs, water (r2 = 0.96), methanol (r2 = 0.95), 4-fluorophenol (r2 = 0.91), serine (r2 = 0.93), and methylamine (r2 = 0.97). The connection between experiment and computation was strengthened with the finding that there is no relationship between ΔE(H) and pKBHX when hydrogen fluoride was used as the HBD. Using the methanol model, pKBHX predictions were made for an external set of bases yielding r2 = 0.90. Furthermore, the basicities of polyfunctional bases correlate with ΔE(H), giving r2 = 0.93. This model is promising for the future of computation in fragment-based drug design. Not only has a model been established that links computation to experiment, but the model may also be extrapolated to predict external experimental pKBHX values.

[1]  A. Fersht,et al.  Hydrogen bonding and biological specificity analysed by protein engineering , 1985, Nature.

[2]  Beat Ernst,et al.  Drug discovery today. , 2003, Current topics in medicinal chemistry.

[3]  Michael H. Abraham,et al.  Linear solvation energy relationships. 23. A comprehensive collection of the solvatochromic parameters, .pi.*, .alpha., and .beta., and some methods for simplifying the generalized solvatochromic equation , 1983 .

[4]  Paul L. A. Popelier,et al.  MORPHY, a program for an automated “atoms in molecules” analysis , 1996 .

[5]  Michael H. Abraham,et al.  Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes , 2010 .

[6]  Paul L. A. Popelier,et al.  Atoms in Molecules: An Introduction , 2000 .

[7]  Olivier Lamarche,et al.  Atoms in molecules investigation of the pKHB basicity scale: electrostatic and covalent effects in hydrogen bonding , 2003 .

[8]  Hydrogen-bonded complex formation with 5-fluoroindole. Applications of the pKHB scale , 1972 .

[9]  E. LaVoie,et al.  Bioisosterism: A Rational Approach in Drug Design. , 1996, Chemical reviews.

[10]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[11]  Markus Wagener,et al.  The Quest for Bioisosteric Replacements , 2006, J. Chem. Inf. Model..

[12]  M. Berthelot,et al.  Structure and molecular interactions of anti-thyroid drugs. Part 2. Electron donor properties of carbimazole1 , 1998 .

[13]  Paul L. A. Popelier,et al.  A ROBUST ALGORITHM TO LOCATE AUTOMATICALLY ALL TYPES OF CRITICAL-POINTS IN THE CHARGE-DENSITY AND ITS LAPLACIAN , 1994 .

[14]  M. Berthelot,et al.  THE HYDROGEN-BOND BASICITY PKHB SCALE OF PEROXIDES AND ETHERS , 1998 .

[15]  Richard A. Lewis,et al.  Three-dimensional pharmacophore methods in drug discovery. , 2010, Journal of medicinal chemistry.

[16]  S. F. Boys,et al.  The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors , 1970 .

[17]  Michael H. Abraham,et al.  Solubility properties in polymers and biological media. 4. Correlation of octanol/water partition coefficients with solvatochromic parameters , 1984 .

[18]  M. Berthelot,et al.  Hydrogen-bond basicity of secondary and tertiary amides, carbamates, ureas and lactams , 1992 .

[19]  L. M. Lima,et al.  Bioisosterism: a useful strategy for molecular modification and drug design. , 2005, Current medicinal chemistry.

[20]  B. Kuhn,et al.  Intramolecular hydrogen bonding in medicinal chemistry. , 2010, Journal of medicinal chemistry.

[21]  Donald G Truhlar,et al.  Design of density functionals that are broadly accurate for thermochemistry, thermochemical kinetics, and nonbonded interactions. , 2005, The journal of physical chemistry. A.

[22]  Donald G Truhlar,et al.  Benchmark Databases for Nonbonded Interactions and Their Use To Test Density Functional Theory. , 2005, Journal of chemical theory and computation.

[23]  Donald G. Truhlar,et al.  Hybrid Meta Density Functional Theory Methods for Thermochemistry, Thermochemical Kinetics, and Noncovalent Interactions: The MPW1B95 and MPWB1K Models and Comparative Assessments for Hydrogen Bonding and van der Waals Interactions , 2004 .

[24]  Adam Ibrahim,et al.  Application of hydrogen bonding calculations in property based drug design. , 2002, Drug discovery today.

[25]  Robert P. Sheridan,et al.  The Most Common Chemical Replacements in Drug-Like Compounds , 2002, J. Chem. Inf. Comput. Sci..

[26]  Wendy A. Warr,et al.  Fragment-based drug discovery , 2009, J. Comput. Aided Mol. Des..

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

[28]  Paul L. A. Popelier,et al.  Geometrically faithful homeomorphisms between the electron density and the bare nuclear potential , 2009 .

[29]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[30]  M. Abraham,et al.  The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatography , 1987 .

[31]  E. Freire.  Do enthalpy and entropy distinguish first in class from best in class? , 2008, Drug discovery today.

[32]  M. Congreve,et al.  Recent developments in fragment-based drug discovery. , 2008, Journal of medicinal chemistry.

[33]  Peter Politzer,et al.  Correlations between molecular electrostatic potentials and some experimentally-based indices of reactivity , 1992 .

[34]  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 .

[35]  C. Thornber,et al.  Isosterism and molecular modification in drug design , 1979 .

[36]  M. Berthelot,et al.  HYDROGEN-BOND BASICITY PKHB SCALE OF SIX-MEMBERED AROMATIC N-HETEROCYCLES , 1998 .

[37]  P. Hajduk,et al.  A decade of fragment-based drug design: strategic advances and lessons learned , 2007, Nature Reviews Drug Discovery.

[38]  A. Reuter,et al.  Hydrogen-Bond Donating and Dipolarity/Polarizability Properties of Chemically Functionalized Silica Particles , 1999 .

[39]  J. Platts.  Theoretical prediction of hydrogen bond basicity , 2000 .

[40]  J. Murray,et al.  Correlations between the solvent hydrogen-bond-donating parameter .alpha. and the calculated molecular surface electrostatic potential , 1991 .

[41]  H. Hagelin,et al.  Family-independent relationships between computed molecular surface quantities and solute hydrogen bond acidity/basicity and solute-induced methanol O–H infrared frequency shifts , 1995 .

[42]  R. Taft,et al.  Effects of polar aprotic solvents on linear free-energy relations in hydrogen-bonded complex formation , 1972 .

[43]  Michael Devereux,et al.  Quantum Isostere Database: A Web-Based Tool Using Quantum Chemical Topology To Predict Bioisosteric Replacements for Drug Design , 2009, J. Chem. Inf. Model..

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

[45]  Paul L A Popelier,et al.  A refined model for prediction of hydrogen bond acidity and basicity parameters from quantum chemical molecular descriptors. , 2009, Physical chemistry chemical physics : PCCP.

[46]  A. Daniel Boese,et al.  Predicting the binding energies of H-bonded complexes: A comparative DFT study , 1999 .

[47]  R. Bader.  Atoms in molecules : a quantum theory , 1990 .

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

[49]  E. Freire,et al.  A Thermodynamic Approach to the Affinity Optimization of Drug Candidates , 2009, Chemical biology & drug design.

[50]  P. Popelier,et al.  Atomic properties of amino acids: computed atom types as a guide for future force-field design. , 2003, Chemphyschem : a European journal of chemical physics and physical chemistry.

[51]  Michael H. Abraham,et al.  Hydrogen bonding. 31. Construction of a scale of solute effective or summation hydrogen‐bond basicity , 1993 .

[52]  R. Bader.  Atoms in molecules , 1990 .

[53]  Oleg A. Raevsky,et al.  Quantitative estimation of hydrogen bond contribution to permeability and absorption processes of some chemicals and drugs , 1998 .

[54]  Klaus R. Liedl,et al.  Theoretical Prediction of Hydrogen Bond Strength for Use in Molecular Modeling , 2009, J. Chem. Inf. Model..