Abstract：
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 c and f were identified as potent inhibitors of 4-hydroxyphenylpyruvate dioxygenase.
摘要：
碱性尿症（AKU）是一种罕见的遗传性常染色体隐性遗传疾病，其特征是血清匀浆酸（HGA）水平升高。在这种疾病中,酪氨酸代谢由于匀浆双加氧酶（HGD）基因的改变而中断。病人患有慢性疾病,骨折,肌腱断裂.迄今为止,目前尚无药物被批准用于治疗AKU.然而,物理治疗和强效止痛药的管理，以帮助减轻病情。最近,尼替辛酮,FDA批准的1型酪氨酸血症药物，已在一些国家给予AKU患者，并在减少疾病进展方面显示出令人鼓舞的结果。然而,这种药物不是AKU的靶向治疗，并导致角膜病变。因此,本研究的首要目的是通过靶向4-羟基苯丙酮酸双加氧酶,鉴定有效且可作为药物的AKU抑制剂,且无副作用或副作用最小.为了实现我们的目标，我们已经使用BioSolveIT套装进行了计算建模。用于分子对接的配体文库通过ReCore对参考分子的片段置换来获得。随后，点击量是根据估计的亲和力进行筛选的，并使用SwissADME评估其药代动力学特性。之后,使用DiscoveryStudio研究了靶标与配体之间的相互作用.最终,化合物c和f被鉴定为4-羟基苯基丙酮酸双加氧酶的有效抑制剂。
