The pKBHX Database: Toward a Better Understanding of Hydrogen-Bond Basicity for Medicinal Chemists

Abstract

The hydrogen bond (HB) is one of the fundamental noncovalent interactions between a drug molecule and its local environment. For drug molecules, this local environment may be a biological target, a biological off-target, aqueous solution, a lipid membrane, or even a crystalline solid. Consequently, hydrogen bonding impacts a wide range of molecular properties critical to drug design including potency, selectivity, and permeability and solubility. Despite its importance, it is the authors’ experience that in general the medicinal chemistry community has a poor intuition for the relative basicity (i.e., strengths) of hydrogen-bond acceptors. In an attempt to assess the relative hydrogen-bond basicities of functional groups, it is common practice to resort to a simple correlation with pKBH, 8 which is generally incorrect and holds true only for closely related compounds in a series (i.e., a family dependent relationship). There is also a tendency to view hydrogen-bond acceptors as atomic sites and to consider them equivalent while disregarding the effects of organic functions and substituents that define the local molecular environment. This is evident in the lack of consideration for exploring hydrogen-bond basicity as an SAR parameter, as is commonly done to establish preferred steric, polar, basic, and acidic moieties. This poor intuition may partly stem from the lack of experimentally observable physical properties that are directly attributed to relative hydrogen-bondbasicities.Furthermore, despite thewell-known role of hydrogen bonds in protein-ligand interactions and the fact that hydrogen bonds are qualitatively well understood, it is generally admitted that quantitative data are needed. In the second section of this paper we review hydrogenbond basicity scales in general and introduce the pKBHX scale with a brief thermodynamic discussion on the treatment of polyfunctional compounds. In section 3 we discuss the effects of a medium more polar than the definition solvent CCl4 and changes in the reference HB donor on the pKBHX scale. In section 4, we present the pKBHX database and describe the fields of each entry,which correspond to threemain categories of data: HBA identification, thermodynamic, and spectroscopic. In section 5 we show that the pKBHX scale of HB basicity differs considerably from the pKBH scale of proton transfer basicity. This is important formedicinal chemistswho have a good knowledge of Broensted proton basicity scales and incorrectly consider HB basicity and proton basicity scales as equivalent. Section 6 reviews the hydrogen-bond basicities of functional groups relevant to medicinal chemistry while considering factors that modulate these values. Section 7 extends this medicinal chemistry discussion by providing examples of the role of hydrogen-bond basicity in properties of interest for drug design and briefly reviews computational approaches for addressing hydrogen bonding.