Department of Chemistry, Molecular Modeling Research Laboratory, Osmania University, Hyderabad, Telangana, 500007, India.
Department of Chemistry, University College of Science, Saifabad, Osmania University, Hyderabad, Telangana, 500004, India.
Curr Protein Pept Sci. 2023;24(7):589-609. doi: 10.2174/1389203724666230713124339.
The present work considers the Sulphate import ABC transporter protein (cysA) as a potential drug target for the identification of inhibitors for the protein.
The ABC (ATP binding cassette) transporters play a crucial role in the survival and virulence of by the acquisition of micronutrients from host tissue.
The 3D structural features of the cysA protein are built. Molecular scaffolds are identified by implementing active site identification, ADME properties, Virtual Screening, and a few other computational techniques.
The theoretical model of cysA is predicted using homology modeling protocols, and the structure is validated by various validation methods. The prediction of partial dimer formation through protein-protein docking methods gave insight into the conformational changes taking place in the cysA protein. The natural substrate ATP is docked with cysA protein that confirms the ATP binding site. To find the drug-like compounds, virtual screening studies were carried out around the active site by several ligand databases.
The findings demonstrate the significance of residues SER41, GLY42, ARG50, GLN85, HIS86, LYS91, ARG142, and ASP161 in drug-target interactions. The docking studies of existing TB drugs against cysA were also performed. The result analysis shows that none of the existing drugs inhibits the ATP active site, which confirms cysA as a promising drug target. Using in-silico methods, the ADME parameters of a few chosen ligand molecules are predicted and contrasted with the ADME characteristics of the available TB medications.
The results revealed the values of ADME parameters of selected ligand molecules are more permissible than existing TB drugs, which emphasizes the drug-like activity of ligand molecules by inhibition of cysA proteins. The structural data, active site information, and selected ligand molecules help in the identification of new therapeutic scaffolds for Tuberculosis.
本研究将硫酸盐进口 ABC 转运蛋白（cysA）视为一种潜在的药物靶点，以鉴定该蛋白的抑制剂。
ABC（ATP 结合盒）转运蛋白在从宿主组织获取微量元素方面对 的生存和毒力起着至关重要的作用。
构建 cysA 蛋白的 3D 结构特征。通过实施活性位点识别、ADME 特性、虚拟筛选和其他一些计算技术，确定分子支架。
使用同源建模方案预测 cysA 的理论模型，并通过各种验证方法验证结构。通过蛋白质-蛋白质对接方法预测部分二聚体的形成，深入了解 cysA 蛋白发生的构象变化。将天然底物 ATP 与 cysA 蛋白对接，以确认 ATP 结合位点。为了找到类似药物的化合物，通过几个配体数据库在活性位点周围进行虚拟筛选研究。
研究结果表明，残基 SER41、GLY42、ARG50、GLN85、HIS86、LYS91、ARG142 和 ASP161 在药物-靶标相互作用中具有重要意义。还对现有的 TB 药物与 cysA 的对接研究进行了研究。结果分析表明，现有的药物都没有抑制 ATP 活性位点，这证实了 cysA 是一个有前途的药物靶点。通过计算机模拟方法，预测了几个选定配体分子的 ADME 参数，并与现有的 TB 药物的 ADME 特征进行了对比。
结果表明，所选配体分子的 ADME 参数值比现有的 TB 药物更允许，这强调了通过抑制 cysA 蛋白，配体分子具有类似药物的活性。结构数据、活性位点信息和选定的配体分子有助于确定结核病的新治疗支架。
