Department of Biotechnology, Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education and Research (DU), Porur, Chennai, Tamil Nadu, 600116, India.
Faculty of Allied Health Sciences, Meenakshi Academy of Higher Education, Chennai, India.
Mol Divers. 2024 Aug;28(4):2049-2063. doi: 10.1007/s11030-023-10694-8. Epub 2023 Jul 17.
Mucopolysaccharidoses VI (Maroteaux Lamy syndrome) is a metabolic disorder due to the loss of enzyme activity of N-acetyl galactosamine-4-sulphatase arising from mutations in the ARSB gene. The mutated ARSB is the origin for the accumulation of GAGs within the lysosome leading to severe growth deformities, causing lysosomal storage disease. The main focus of this study is to identify the deleterious variants by applying bioinformatics tools to predict the conservation, pathogenicity, stability, and effect of the ARSB variants. We examined 170 missense variants, of which G137V and G144R were the resultant variants predicted detrimental to the progression of the disease. The native along with G137V and G144R structures were fixed as the receptors and subjected to Molecular docking with the small molecule Odiparcil to analyze the binding efficiency and the varied interactions of the receptors towards the drug. The interaction resulted in similar docking scores of - 7.3 kcal/mol indicating effective binding and consistent interactions of the drug with residues CYS117, GLN118, THR182, and GLN517 for native, along with G137V and G144R structures. Molecular Dynamics were conducted to validate the stability and flexibility of the native and variant structures on ligand binding. The overall study indicates that the drug has similar therapeutic towards the native and variant based on the higher binding affinity and also the complexes show stability with an average of 0.2 nm RMS value. This can aid in the future development therapeutics for the Maroteaux Lamy syndrome.
黏多糖贮积症 VI（马罗托克斯-拉米综合征）是一种代谢紊乱，由于 ARSB 基因的突变导致 N-乙酰半乳糖胺-4-硫酸酯酶活性丧失。突变的 ARSB 是溶酶体中 GAG 积累的起源，导致严重的生长畸形，从而引发溶酶体贮积症。本研究的主要重点是应用生物信息学工具识别有害变异体，以预测 ARSB 变异体的保守性、致病性、稳定性和效应。我们检查了 170 种错义变异体，其中 G137V 和 G144R 是预测对疾病进展有害的结果变异体。天然结构以及 G137V 和 G144R 结构被固定为受体，并与小分子 Odiparcil 进行分子对接，以分析受体与药物的结合效率和变化的相互作用。相互作用导致类似的对接评分-7.3 kcal/mol，表明药物与天然结构以及 G137V 和 G144R 结构的残基 CYS117、GLN118、THR182 和 GLN517 有效结合和一致相互作用。进行分子动力学模拟以验证天然和变体结构在配体结合时的稳定性和灵活性。总体研究表明，该药物对天然和变体具有相似的治疗作用，这是基于更高的结合亲和力，并且复合物显示出稳定性，平均 RMS 值为 0.2 nm。这可以有助于未来开发马罗托克斯-拉米综合征的治疗方法。
