DataSheet1_Molecular Structural, Hydrogen Bonding Interactions, and Chemical Reactivity Studies of Ezetimibe-L-Proline Cocrystal Using Spectroscopic and Quantum Chemical Approach.docx

Ezetimibe (EZT) being an anticholesterol drug is frequently used for the reduction of elevated blood cholesterol levels. With the purpose of improving the physicochemical properties of EZT, in the present study, cocrystals of ezetimibe with L-proline have been studied. Theoretical geometry optimization of EZT-L-proline cocrystal, energies, and structure–activity relationship was carried out at the DFT level of theory using B3LYP functional complemented by 6-311++G(d,p) basis set. To better understand the role of hydrogen bonding, two different models (EZT + L-proline and EZT + 2L-proline) of EZT-L-proline cocrystal were studied. Spectral techniques (FTIR and FT-Raman) combined with quantum chemical methodologies were successfully implemented for the detailed vibrational assignment of fundamental modes. It is a zwitterionic cocrystal hydrogen bonded with the OH group of EZT and the COO− group of L-proline. The existence and strength of hydrogen bonds were examined by a natural bond orbital analysis (NBO) supported by the quantum theory of atoms in molecule (QTAIM). Chemical reactivity was reflected by the HOMO–LUMO analysis. A smaller energy gap in the cocrystal in comparison to API shows that a cocrystal is softer and chemically more reactive. MEPS and Fukui functions revealed the reactive sites of cocrystals. The calculated binding energy of the cocrystal from counterpoise method was −11.44 kcal/mol (EZT + L-proline) and −26.19 kcal/mol (EZT + 2L-proline). The comparative study between EZT-L-proline and EZT suggest that cocrystals can be better used as an alternative to comprehend the effect of hydrogen bonding in biomolecules and enhance the pharmacological properties of active pharmaceutical ingredients (APIs).

Ezetimibe（简称EZT）作为一种降胆固醇药物，常用于降低高血脂水平。本研究旨在提升EZT的物化性质，因此对EZT与L-脯氨酸的共晶进行了研究。采用密度泛函理论（DFT）的B3LYP泛函以及6-311++G(d,p)基组，对EZT-L-脯氨酸共晶进行了理论几何优化、能量计算以及构效关系分析。为了深入理解氢键的作用，研究了两种不同的EZT-L-脯氨酸共晶模型（EZT + L-脯氨酸和EZT + 2L-脯氨酸）。通过结合光谱技术（FTIR和FT-Raman）与量子化学方法，对共晶的基本振动模式进行了详细的归属。该共晶是一种两性离子型氢键化合物，通过EZT的OH基团与L-脯氨酸的COO−基团相互作用而成。通过自然键轨道分析（NBO）和分子原子量子理论（QTAIM）支持的氢键存在性和强度得到了验证。化学活性通过HOMO-LUMO分析得到反映。与API相比，共晶中较小的能隙表明共晶具有更柔软的物理性质和更高的化学活性。MEPS和福居函数揭示了共晶的活性位点。通过对比方法计算得到的共晶结合能为（EZT + L-脯氨酸）-11.44 kcal/mol和（EZT + 2L-脯氨酸）-26.19 kcal/mol。比较EZT-L-脯氨酸与EZT的研究表明，共晶可作为替代品更好地理解生物大分子中氢键的作用，并增强活性药物成分（APIs）的药理性质。