title: Hydrogen-Bond Accepting Properties of New Heteroaromatic Ring Chemical Motifs: A Theoretical Study.
abstract: The prediction of hydrogen-bond (H-bond) acceptor ability is crucial in drug design. This important property is quantified in a large pKBHX database of consistently measured values. We aim to expand the chemical diversity of the studied H-bond acceptors and to increase the range of H-bond strength considered. Two quantum chemical descriptors are contrasted, called ΔE(H) (the change in the energy of a topological hydrogen atom upon complexation) and Vmin (the local minimum in the electrostatic potential on the H-bond accepting site). We performed a systematic analysis of the correlations between pKBHX and Vmin for an initial set of 106 compounds (including O- and N-containing subsets, as well as compounds including sulfur, chlorine, and π-bases). Correlations improve for family dependent subsets, and after outlier treatment, a set of 90 compounds was used to set up a linear equation to predict pKBHX from Vmin. This equation and a previously published equation [Green and Popelier J. Chem. Inf.
  
  
  METHODS
  2014, 54 (2), 553-561], to predict pKBHX from ΔE(H), were used to predict the pKBHX values for 22 potentially biologically active heteroaromatic ring compounds, [Pitt et al. J. Med. Chem. 2009, 52 (9), 2952-2963], among which several structures still remain experimentally unavailable. H-Bond basicity of sp(2) nitrogen sites were consistently predicted with both descriptors. A worse agreement was found with carbonyl acceptor sites, with the stronger deviations observed for the lactam groups. It was shown that secondary interactions involving the neighboring NH group were influencing the results. Substitution of the NH group with an NMe group resulted in an improved consistency from both Vmin and ΔE(H) predictions, the latter being more prominently affected by the methyl substitution. Both approaches appear as efficient procedures for the H-bond ability prediction of novel heteroaromatic rings. Nevertheless, the ΔE(H) parameter presents slight chemical structure limitations and requires more detailed H-bond structure investigations.
authors.affiliation: Chimie et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UMR CNRS 6230, Université de Nantes , 2 rue de la Houssinière-BP 92208, 44322 Nantes Cedex 3, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Graton
authors.affiliation: Chimie et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UMR CNRS 6230, Université de Nantes , 2 rue de la Houssinière-BP 92208, 44322 Nantes Cedex 3, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Questel
authors.affiliation: Manchester Institute of Biotechnology (MIB) , 131 Princess Street, Manchester M1 7DN, Great Britain.|School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, Great Britain.
authors.forename: Peter
authors.initials: P
authors.lastname: Maxwell
authors.affiliation: Manchester Institute of Biotechnology (MIB) , 131 Princess Street, Manchester M1 7DN, Great Britain.|School of Chemistry, University of Manchester , Oxford Road, Manchester M13 9PL, Great Britain.
authors.forename: Paul
authors.initials: P
authors.lastname: Popelier
mesh_terms: D003500:Cyclization; D006838:Hydrocarbons / Q000737:chemistry*; D006860:Hydrogen Bonding; D008962:Models, Theoretical
chemical_list: D006838:Hydrocarbons