Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics

Abstract

Protein crystallography and calorimetry were used to characterize the binding of 1,2-azaborines to model cavities in T4 lysozyme in direct comparison to their carbonaceous counterparts. In the apolar L99A cavity, affinity for Ab dropped only slightly versus benzene. In the cavity designed to accommodate a single hydrogen bond (L99A/M102Q), Gln102=O⋯H—N hydrogen bonding for Ab and BEtAb was observed in the crystallographic complexes. The strength of the hydrogen bonding was estimated as 0.94 and 0.64 kcal/mol for Ab and BEtAb, respectively. This work unambiguously demonstrates that 1,2-azaborines can be readily accommodated in classic aryl recognition pockets and establishes one of 1,2-azaborine’s distinguishing features from its carbonaceous isostere benzene: its ability to serve as an NH hydrogen bond donor in a biological setting.

Interaction of Non‐polarizable Cations with Azaborine Isomers and Their Mono‐Substituted Derivatives: Position, Induction, and Non‐Classical Effects Matter

“…In line with our work and Alkorta et al . study, Lee et al . have shown experimentally that 1,2‐azaborine may be inserted into the T4 Lysozyme mutant cavity through the O⋅⋅⋅H−N contact, what is of importance in classical aryl recognition pockets.…”

Medicinal Chemistry Profiling of Monocyclic 1,2‐Azaborines

“…BN/CC isosterism of arenes results in the so‐called azaborine heterocycles where specifically 1,2‐azaborines are designated as compounds with the boron and nitrogen atoms adjacent to each other (Figure ) . It has been demonstrated that 1,2‐azaborines can bind to aryl recognition pockets in biological targets and engage in hydrogen bonding inside those binding pockets . Furthermore, it has been shown that both the B ‐ and N ‐Et BN isosteres of ethylbenzene are inhibitors of ethylbenzene dehydrogenase (EbDH), in contrast to ethylbenzene itself, which is the naturally evolved substrate for the EbDH .…”

“…6 It has been demonstrated that 1,2-azaborines can bind to aryl recognition pockets 7 in biological targets and engage in hydrogen bonding inside those binding pockets. 8 Furthermore, it has been shown that both the B - and N -Et BN isosteres of ethylbenzene are inhibitors of ethylbenzene dehydrogenase (EbDH), in contrast to ethylbenzene itself, which is the naturally evolved substrate for the EbDH. 9 Despite the recent advances made in the area of azaborine chemistry, 10 the progress toward evaluating these heterocycles in the context of medicinal chemistry has remained underexplored.…”

“…The 3–4 fold improvement in binding of BN-3 vs. CC-3 may be attributed to this NH…O=C(amide) hydrogen bonding which we have recently quantified to be ~ 1 kcal/mol in strength (in the context of binding to T4 Lysozymes). 8 …”

Inorganic Triphenylphosphine

“…The diatomic fragments BN and CC are isoelectronic and the chemical consequences of this simple relationship have been appreciated ever since the 1926 discovery of borazine which is isoelectronic to benzene and dubbed “inorganic benzene” (Figure ) . The substitution of a BN unit for a CC in an organic molecule has a transformative effect on the properties of the compound as illustrated by the three comparisons given in Figure from the fields of photochemistry, medicinal chemistry and hydrogen storage …”