Low water solubility of candidate drug compounds is a major problem in pharmaceutical research and development. We developed a novel drug delivery system (DDS) for poorly water-soluble drugs using lipocalin-type prostaglandin D synthase (L-PGDS), which belongs to the lipocalin superfamily and binds a large variety of hydrophobic molecules. In this study, we comprehensively evaluated the capability of L-PGDS to bind and solubilize various poorly water-soluble drugs using structure-based docking. Docking simulations of 2892 commercially available approved drugs indicated that L-PGDS shows higher binding affinities for various drugs compared with 2-hydroxypropyl-β-cyclodextrin. Five drugs selected from the top 100 with the highest binding affinities for L-PGDS exhibited very low solubility in PBS (pH 7.4). However, in the presence of 1 mM L-PGDS, the apparent solubility of all drugs improved markedly, from 19.5- to 166-fold. Calorimetric experiments on two drugs, telmisartan and imatinib, revealed that L-PGDS forms a 1:2 complex with each drug, with dissociation constants of 0.4–40.0 μM. Kinetic simulations of drug dissolution with L-PGDS indicated that the difference in free energy change (ΔΔG) between the insoluble state and the L-PGDS–bound state are within the range from −10 to +5 kJ mol^–1. The ΔΔG value is a critical factor in evaluating whether a poorly water-soluble drug can be solubilized by L-PGDS. Collectively, these results demonstrate that in silico docking is a promising approach for identifying drug molecules suitable for the L-PGDS-based DDS.

中文翻译：

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脂联素型前列腺素D合酶与水溶性差的药物的结合的综合评价

候选药物化合物的低水溶性是药物研究和开发中的主要问题。我们使用脂环素型前列腺素D合酶（L-PGDS）开发了一种水溶性差的药物的新型药物递送系统（DDS），该酶属于脂环素超家族并结合了多种疏水分子。在这项研究中，我们使用基于结构的对接综合评估了L-PGDS结合和溶解各种水溶性差的药物的能力。对2892个可商购获得批准的药物的对接模拟表明，与2-羟丙基-β-环糊精相比，L-PGDS对多种药物具有更高的结合亲和力。从前100种药物中，对L-PGDS的结合亲和力最高的五种药物在PBS（pH 7.4）中的溶解度非常低。但是，在存在1 mM L-PGDS的情况下，所有药物的表观溶解度均显着提高，从19.5倍提高到166倍。对两种药物替米沙坦和伊马替尼的量热实验表明，L-PGDS与每种药物形成1：2的络合物，解离常数为0.4–40.0μM。用L-PGDS进行药物溶解的动力学模拟表明，自由能变化的差异（ΔΔ在不溶状态和L-PGDS结合状态之间的G）在-10至+5 kJ mol ^–1的范围内。的ΔΔ ģ值是在评估是否一个水难溶性药物可以通过L-PGDS被溶解的关键因素。总体而言，这些结果表明，计算机对接技术是用于鉴定适用于基于L-PGDS的DDS的药物分子的有前途的方法。