Understanding the Boron–Nitrogen Interaction
and Its Possible Implications in Drug Design
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Abstract
2-Aminoethoxydiphenylborate
(2-APB) is a broad-spectrum modulator
of various membrane proteins. Specifically, it exhibits concentration
dependent modulation of calcium signaling through store-operated calcium
(SOC) channels: low micromolar concentration of 2-APB stimulates SOC
entry while a higher concentration induces complete inhibition. Ab
initio quantum chemical calculations show that the relative stability
of the two major isomers of 2-APB (cyclic and extended) is about 8
kcal/mol. The dual functionality of 2-APB for SOC channels is thus
likely associated with its ability to switch among isomeric forms,
suited to different binding sites in the SOC channels with distinct
binding affinities. Importantly, the moderate relative stability of
different isomers results from a delicate balance between the intramolecular
boron–nitrogen coordinate bond with strength about −45
kcal/mol and ring strain engendered by cyclic oligomerization. The
synergistic effect of these two factors likely makes 2-APB an ideal
dual effect drug