Department of Pharmaceutical and Medicinal, University of Nigeria, Nsukka, Nigeria.
Department of Biotechnology, Vellore Institute of Technology, Vellore, Tamilnadu, India.
J Biomol Struct Dyn. 2023 Jul;41(10):4811-4818. doi: 10.1080/07391102.2022.2064916. Epub 2022 Apr 25.
Dolichyl-phosphate N-acetylglucosaminephosphotransferase (dpagt1) inhibition is reported to kill tumor cells whose growth progression requires increased branching of N-linked glycans. Available dpagt1 inhibitors are grossly limited and are faced with problems of heamolytic effect and aqueous solubility thereby necessitating the search for new, safe and effective dpagt1 inhibitors. We employed computational methods to screen a dataset of ∼1300 FDA approved drugs in order to obtain theoretical dpagt1 inhibitors which could be repurposed as chemotherapeutic drugs. Top six better performing drugs, binding affinity for dpagt1 at the range of -17.63 to -20.40 kcal/mol, than the reference ligand (tunicamycin; -14.86 kcal/mol) were obtained at the end of structure-based-pharmacophore- and virtual-screening and 'induced fit' docking calculations. Analysis of their binding poses identified essential pharmacophores involved in target-ligand complexation that could be targeted in chemical modification to develop more effective and safe dpagt1 inhibitors.Communicated by Ramaswamy H. Sarma.
磷酸多萜醇-N-乙酰葡萄糖胺磷酸转移酶（dpagt1）抑制剂被报道可杀死那些生长进展需要增加 N-连接聚糖分支的肿瘤细胞。现有的 dpagt1 抑制剂受到严重限制，并且存在溶血作用和水溶性问题，因此需要寻找新的、安全有效的 dpagt1 抑制剂。我们采用计算方法筛选了大约 1300 种 FDA 批准的药物数据集，以获得可重新用于化疗药物的理论 dpagt1 抑制剂。在结构基于药效团和虚拟筛选以及“诱导契合”对接计算之后，得到了六个表现更好的药物，它们与 dpagt1 的结合亲和力在-17.63 到-20.40 kcal/mol 的范围内，优于参考配体（衣霉素；-14.86 kcal/mol）。对它们的结合构象进行分析，确定了参与靶标-配体复合物形成的必需药效团，这些药效团可以作为化学修饰的靶点，以开发更有效和安全的 dpagt1 抑制剂。由 Ramaswamy H. Sarma 传达。
