Revealing Local Structure of Angiotensin Receptor-Neprilysin Inhibitor (S086) Drug Cocrystal by Linear and Nonlinear Infrared Spectroscopies.

Structurally knowing the active sites of a drug is important for understanding its therapeutic functions. S086 is a novel angiotensin receptor-neprilysin inhibitor that consists of the molecular moieties of EXP3174 (the active metabolite of the angiotensin receptor blocker losartan) and sacubitril (a neprilysin inhibitor prodrug) in a 1:1 molar ratio. There are two forms of cocrystals of S086, namely, ξ-crystal and α-crystal, which were formed both via intermolecular coordination bonding to calcium ions, with the aid of internal water. The binding state of multiple carboxyl anions (COO) to Ca of EXP3174 and sacubitril was examined in this study using infrared (IR) absorption spectroscopy, in which the asymmetric stretching () and symmetric stretching () modes of the COO groups were used as IR probes. Ultrafast two-dimensional (2D) IR spectroscopy was utilized for spectrally assigning the origin of multiple COO groups by the presence or absence of interchromophore vibrational coupling. Key structural variation between the two crystal forms was found: in the unit cell of ξ-crystal, the ratio of "bridging" and "bidentate" types of COO binding to Ca for four EXP3174 molecules is 2:2, while the ratio is predicted to be 3:1 in the case of α-crystal. However, in both crystals, four sacubitril molecules are believed to similarly form a "trident" type of COO binding to Ca. Our study demonstrates that linear and nonlinear IR spectroscopies can be used to characterize local crystal structures of drugs and reveal subtle difference between similar crystal structures.