Singh Vijai, Somvanshi Pallavi
Bioinformatics Centre, Biotech Park, Lucknow, India.
Protein Pept Lett. 2010 Feb;17(2):269-76. doi: 10.2174/092986610790225950.
DNA ligase is an important enzyme and it plays vital role in the replication and repair; also catalyzes nick joining between adjacent bases of DNA. The NAD(+) dependent DNA ligase is selectively present in eubacteria and few viruses; but missing in humans. Homology modeling was used to generate 3-D structure of NAD(+) dependent DNA ligase (LigA) of Mycobacterium tuberculosis using the known template (PDB: 2OWO). Furthermore, the stereochemical quality and torsion angle of 3-D structure was validated. Numerous effective drugs were selected and the active amino acid residue in LigA was targeted and virtual screening through molecular docking was done. In this analysis, four drugs Chloroquine, Hydroxychloroquine, Putrienscine and Adriamycin were found more potent in inhibition of M. tuberculosis through the robust binding affinity between protein-drug interactions in comparison with the other studied drugs. A phylogenetic tree was constructed and it was observed that homology of LigA in M. tuberculosis resembled with other Mycobacterium species. The conserved active amino acids of LigA may be useful to target these drugs. These findings could be used as the starting point of a rational design of novel antibacterial drugs and its analogs.
DNA连接酶是一种重要的酶，在复制和修复过程中发挥着至关重要的作用；它还催化DNA相邻碱基之间的切口连接。依赖NAD(+)的DNA连接酶选择性地存在于真细菌和少数病毒中；但在人类中不存在。利用已知模板（PDB：2OWO）通过同源建模生成结核分枝杆菌依赖NAD(+)的DNA连接酶（LigA）的三维结构。此外，对三维结构的立体化学质量和扭转角进行了验证。筛选了多种有效药物，针对LigA中的活性氨基酸残基进行靶向，并通过分子对接进行虚拟筛选。在该分析中，发现氯喹、羟氯喹、腐胺和阿霉素这四种药物与其他研究药物相比，通过蛋白质-药物相互作用之间强大的结合亲和力，对结核分枝杆菌的抑制作用更强。构建了系统发育树，观察到结核分枝杆菌中LigA的同源性与其他分枝杆菌属物种相似。LigA保守的活性氨基酸可能有助于靶向这些药物。这些发现可作为新型抗菌药物及其类似物合理设计的起点。
