Nayak Tapaswini, Jena Lingaraja, Waghmare Pranita, Harinath Bhaskar C
Bioinformatics Centre, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, Maharashtra, India.
Department of Biochemistry, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, Maharashtra, India.
Int J Mycobacteriol. 2018 Jan-Mar;7(1):61-68. doi: 10.4103/ijmy.ijmy_174_17.
The Mycobacterium tuberculosis (MTB) uridine diphosphogalactofuranose (UDP)-galactopyranose mutase (UGM) is an essential flavoenzyme for mycobacterial viability and an important component of cell wall. It catalyzes the interconversion of UDP-galactopyranose into UDP-galactofuranose, a key building block for cell wall construction, essential for linking the peptidoglycan and mycolic acid cell wall layers in MTB through a 2-keto intermediate. Further, as this enzyme is not present in humans, it is an excellent therapeutic target for MTB. Thus, inhibition of this UGM enzyme is a good approach to explore new anti-TB drug. This study aims to find novel and effective inhibitors against UGM from reported natural phytochemicals and ZINC database using virtual screening approach.
In this study, 148 phytochemicals with reported antitubercular activity and 5280 ZINC compounds with 70% structural similarity with the natural substrate of UGM (UDP-galactopyranose and UDP-galactofuranose) were screened against UGM.
In virtual screening, 19 phytochemicals and 477 ZINC compounds showed comparatively better binding affinity than natural substrates. Among them, best 10 compounds from each group were proposed as potential inhibitors for UGM based on the binding energy and protein-ligand interaction analysis. Among phytochemicals, three compounds, namely, tiliacorine, amentoflavone, and 2'-nortiliacorinine showed highest binding affinity (binding energy of -10.5, -10.4, and -10.3 Kcal/mol, respectively), while among ZINC compounds, ZINC08219848 and ZINC08217649, showing highest binding affinity (binding energy of -10.0 and -9.7 Kcal/mol, respectively) toward UGM as compared to its substrates.
These selected compounds may be proposed as potential inhibitors of UGM and need to be tested in TB culture studies in vitro to assess their anti-TB activity.
结核分枝杆菌（MTB）的尿苷二磷酸半乳糖呋喃糖（UDP）-吡喃半乳糖变位酶（UGM）是一种对分枝杆菌生存至关重要的黄素酶，也是细胞壁的重要组成部分。它催化UDP-吡喃半乳糖转化为UDP-半乳糖呋喃糖，后者是细胞壁构建的关键组成部分，对于通过2-酮中间体连接MTB中的肽聚糖和分枝菌酸细胞壁层至关重要。此外，由于该酶在人类中不存在，它是MTB的一个极佳治疗靶点。因此，抑制这种UGM酶是探索新型抗结核药物的一个好方法。本研究旨在使用虚拟筛选方法从已报道的天然植物化学物质和ZINC数据库中寻找针对UGM的新型有效抑制剂。
在本研究中，针对UGM筛选了148种具有已报道抗结核活性的植物化学物质和5280种与UGM天然底物（UDP-吡喃半乳糖和UDP-半乳糖呋喃糖）具有70%结构相似性的ZINC化合物。
在虚拟筛选中，19种植物化学物质和477种ZINC化合物显示出比天然底物更好的结合亲和力。其中，基于结合能和蛋白质-配体相互作用分析，每组中最佳的10种化合物被提议作为UGM的潜在抑制剂。在植物化学物质中，三种化合物，即蒂巴因、穗花杉双黄酮和2'-去甲蒂巴因显示出最高的结合亲和力（结合能分别为-10.5、-10.4和-10.3千卡/摩尔），而在ZINC化合物中，ZINC08219848和ZINC08217649与底物相比，对UGM显示出最高的结合亲和力（结合能分别为-10.0和-9.7千卡/摩尔）。
这些选定的化合物可能被提议作为UGM的潜在抑制剂，需要在体外结核培养研究中进行测试，以评估它们的抗结核活性。
