In the present study, a novel cocrystal of felodipine (FEL) and β-resorcylic acid (βRA) was developed. We specially focused on the change of binding pattern with bovine serum albumin (BSA) induced by cocrystallization of FEL with βRA. The solid characterizations and density functional theory (DFT) simulation verified that FEL–βRA cocrystal formed in equimolar ratio (1 : 1 M ratio) through C=O^…H–O hydrogen bond between C=O group in FEL and O–H group in βRA. The binding interactions between FEL–βRA system and BSA were studied using fluorescence spectral and molecular docking methods. Two guest molecule systems, including a physical mixture of FEL and βRA and FEL–βRA cocrystal were performed binding to BSA in molecular docking. According to the K_b and binding energy, the supramolecular form of FEL–βRA system was retained during binding to BSA. Molecular docking simulation suggested that FEL and its cocrystal inserted into the subdomain IIIA (site II′) of BSA. The interactions between FEL and BSA including hydrogen bonding with ASN390 residue and intermolecular hydrophobic interactions with LEU429 and LEU452 residues. However, the size of supramolecular FEL–βRA better matched that of active cavity of BSA; the cocrystal is closely bound to BSA through hydrogen bonding with ASN390 residue and intermolecular hydrophobic interactions with LEU429, VAL432, LEU452 and ILE387 residues. This change on binding affinity of FEL to BSA induced by cocrystallization with βRA provided theoretical basis to evaluate the transportation, distribution and metabolism of cocrystal drug.

在本研究中，开发了一种新型的非洛地平（FEL）和β-间苯二酸（βRA）共晶体。我们特别关注由FEL与βRA共结晶引起的与牛血清白蛋白（BSA）结合模式的变化。固体表征和密度泛函理论（DFT）模拟验证了FEL-βRA共结晶以等摩尔比（1：1 M比率）通过C = O ^… FEL中的C = O基团与O–H基团之间的氢键形成在βRA中。使用荧光光谱和分子对接方法研究了FEL–βRA系统与BSA之间的结合相互作用。在分子对接中结合BSA进行了两个客体分子系统，包括FEL和βRA的物理混合物以及FEL-βRA共晶体。根据K _b和结合能，FEL-βRA系统的超分子形式在与BSA结合时得以保留。分子对接模拟表明，FEL及其共晶体插入了BSA的亚域IIIA（位点II'）。FEL和BSA之间的相互作用包括与ASN390残基的氢键结合以及与LEU429和LEU452残基的分子间疏水性相互作用。但是，超分子FEL-βRA的大小与BSA的活动腔更好地匹配；共晶通过与ASN390残基的氢键键合以及与LEU429，VAL432，LEU452和ILE387残基的分子间疏水相互作用与BSA紧密结合。βRA共结晶诱导的FEL与BSA结合亲和力的变化为评价共结晶药物的转运，分布和代谢提供了理论基础。