Department of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University , 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
Research Fellow of the Japan Society for the Promotion of Science , 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan.
Mol Pharm. 2017 Oct 2;14(10):3558-3567. doi: 10.1021/acs.molpharmaceut.7b00590. Epub 2017 Sep 8.
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. 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.
候选药物化合物的低水溶性是药物研发中的一个主要问题。我们使用亲脂素型前列腺素 D 合酶（L-PGDS）开发了一种用于治疗水溶性差的药物的新型药物传递系统（DDS），L-PGDS 属于亲脂素超家族，可结合多种疏水分子。在这项研究中，我们使用基于结构的对接技术全面评估了 L-PGDS 结合和溶解各种水溶性差的药物的能力。对 2892 种市售的已批准药物进行对接模拟表明，与 2-羟丙基-β-环糊精相比，L-PGDS 对各种药物表现出更高的结合亲和力。从与 L-PGDS 结合亲和力最高的前 100 种药物中选择的 5 种药物在 PBS（pH 7.4）中的溶解度非常低。然而，在 1mM L-PGDS 存在下，所有药物的表观溶解度均显著提高，从 19.5 倍提高至 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 的复合物，解离常数为 0.4-40.0μM。使用 L-PGDS 进行药物溶解的动力学模拟表明，不溶性状态与 L-PGDS 结合状态之间的自由能变化（ΔΔG）的差异在-10 至+5kJ/mol 的范围内。ΔΔG 值是评估水溶性差的药物是否可以被 L-PGDS 溶解的关键因素。综上所述，这些结果表明，基于结构的对接是一种很有前途的方法，可以识别适合基于 L-PGDS 的 DDS 的药物分子。
