Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore 54590, Pakistan.
Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University, Al Ain P.O. Box 64141, United Arab Emirates.
Molecules. 2023 Mar 14;28(6):2623. doi: 10.3390/molecules28062623.
Alkaptonuria (AKU) is a rare genetic autosomal recessive disorder characterized by elevated serum levels of homogentisic acid (HGA). In this disease, tyrosine metabolism is interrupted because of the alterations in homogentisate dioxygenase (HGD) gene. The patient suffers from ochronosis, fractures, and tendon ruptures. To date, no medicine has been approved for the treatment of AKU. However, physiotherapy and strong painkillers are administered to help mitigate the condition. Recently, nitisinone, an FDA-approved drug for type 1 tyrosinemia, has been given to AKU patients in some countries and has shown encouraging results in reducing the disease progression. However, this drug is not the targeted treatment for AKU, and causes keratopathy. Therefore, the foremost aim of this study is the identification of potent and druggable inhibitors of AKU with no or minimal side effects by targeting 4-hydroxyphenylpyruvate dioxygenase. To achieve our goal, we have performed computational modelling using BioSolveIT suit. The library of ligands for molecular docking was acquired by fragment replacement of reference molecules by ReCore. Subsequently, the hits were screened on the basis of estimated affinities, and their pharmacokinetic properties were evaluated using SwissADME. Afterward, the interactions between target and ligands were investigated using Discovery Studio. Ultimately, compounds and were identified as potent inhibitors of 4-hydroxyphenylpyruvate dioxygenase.
尿黑酸尿症（AKU）是一种罕见的常染色体隐性遗传疾病，其特征是血清同型半胱氨酸（HGA）水平升高。在这种疾病中，由于同型半胱氨酸双加氧酶（HGD）基因的改变，酪氨酸代谢被中断。患者患有褐黄病、骨折和肌腱断裂。迄今为止，尚无药物被批准用于 AKU 的治疗。然而，物理疗法和强力止痛药被用于帮助减轻病情。最近，FDA 批准用于治疗 1 型酪氨酸血症的尼替西农已在一些国家用于 AKU 患者，并已显示出可降低疾病进展的可喜结果。然而，这种药物不是 AKU 的靶向治疗药物，会引起角膜病。因此，本研究的首要目标是通过靶向 4-羟基苯丙酮酸双加氧酶，确定具有强大和可成药的 AKU 抑制剂，且具有最小的副作用或无副作用。为了实现我们的目标，我们使用 BioSolveIT 套件进行了计算建模。分子对接的配体库是通过参考分子的片段替换由 ReCore 获得的。随后，根据估计的亲和力对命中物进行筛选，并使用 SwissADME 评估其药代动力学特性。之后，使用 Discovery Studio 研究了靶标和配体之间的相互作用。最终，化合物 和 被鉴定为 4-羟基苯丙酮酸双加氧酶的有效抑制剂。
