Table_5_In silico Assessment of Pharmacological Profile of Low Molecular Weight Oligo-Hydroxyalkanoates.docx

Polyhydroxyalkanoates (PHAs) are a large class of polyesters that are biosynthesized by microorganisms at large molecular weights (Mw > 80 kDa) and have a great potential for medical applications because of their recognized biocompatibility. Among PHAs, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(4-hydroxyvalerate), and their copolymers are proposed to be used in biomedicine, but only poly(4-hydroxybutyrate) has been certified for medical application. Along with the hydrolysis of these polymers, low molecular weight oligomers are released typically. In this study, we have used a computational approach to assess the absorption, distribution, metabolism, and excretion (ADME)-Tox profiles of low molecular weight oligomers (≤32 units) consisting of 3-hydroxybutyrate, 4-hydroxybutyrate, 3-hydroxyvalerate, 4-hydroxyvalerate, 3-hydroxybutyrate-co-3-hydroxyvalerate, and the hypothetical PHA consisting of 4-hydroxybutyrate-co-4-hydroxyvalerate. According to our simulations, these oligomers do not show cardiotoxicity, hepatotoxicity, carcinogenicity or mutagenicity, and are neither substrates nor inhibitors of the cytochromes involved in the xenobiotic’s metabolism. They also do not affect the human organic cation transporter 2 (OCT2). However, they are considered to be inhibitors of the organic anion transporters OATP1B1, and OATP1B3. In addition, they may produce eye irritation, and corrosion, skin irritation and have a low antagonistic effect on the androgen receptor.

聚羟基脂肪酸酯（Polyhydroxyalkanoates，简称PHAs）是一类由微生物生物合成的大分子量聚酯（分子量Mw大于80 kDa），由于其公认的生物相容性，在医疗应用领域具有巨大的潜力。在PHAs中，聚（3-羟基丁酸酯）、聚（4-羟基丁酸酯）、聚（3-羟基戊酸酯）、聚（4-羟基戊酸酯）及其共聚物被提议用于生物医药领域，然而，仅有聚（4-羟基丁酸酯）被认证用于医疗应用。伴随这些聚合物的水解，通常会产生低分子量的寡聚物。在本研究中，我们采用计算方法对由3-羟基丁酸酯、4-羟基丁酸酯、3-羟基戊酸酯、4-羟基戊酸酯、3-羟基丁酸酯-3-羟基戊酸酯共聚物以及假设的由4-羟基丁酸酯-4-羟基戊酸酯构成的聚羟基脂肪酸酯的低分子量寡聚物（≤32个单元）的吸收、分布、代谢和排泄（ADME）-毒性谱进行了评估。根据我们的模拟结果，这些寡聚物未显示出心脏毒性、肝毒性、致癌性或致突变性，它们既不是参与异物代谢的细胞色素的底物，也不是抑制剂。此外，它们对人类有机阳离子转运蛋白2（OCT2）无影响。然而，它们被认为是有机阴离子转运蛋白OATP1B1和OATP1B3的抑制剂。此外，它们可能引起眼部刺激、腐蚀、皮肤刺激，并对雄激素受体具有低效的拮抗作用。