抗微生物药物和化学疗法耐药性是最重要的医学问题。然而,新型抗菌和抗癌药物的研究仍然滞后。根据他们报道的医疗应用,DNA小沟结合剂(MGBs)值得探索。在这项研究中,实施基于结构的药物设计方法以产生11种MGB化合物,包括一类新型生物活性炔烃连接的MGBs。利用NCI筛选方案来评估靶MGBs的抗肿瘤活性。此外,各种杀菌,细胞致病性,MIC90,并使用这些MGBs对6种医学相关细菌进行细胞毒性测定:肠沙门氏菌,大肠杆菌,粘质沙雷菌,蜡样芽孢杆菌,肺炎链球菌和化脓性链球菌。此外,分子对接,分子动力学模拟,DNA解链,和等温滴定量热法(ITC)分析用于探索最有效的MGBs与DNA双链体d(CGACTAGTCG)2之间的结合模式和相互作用。NCI结果显示,炔连接的MGBs(26和28)在NCI-60组中表现出最显著的生长抑制。此外,化合物MGB3、MGB4、MGB28和MGB32均表现出显著的杀菌效果,抑制蜡样芽孢杆菌和肠球菌介导的细胞致病性,并表现出低细胞毒性。MGB28和MGB32表现出对化脓性链球菌的显著抑制,而MGB28显着抑制粘质链球菌,所有四种小沟粘合剂均显着抑制蜡状芽孢杆菌。这些化合物与DNA结合并扭曲其凹槽尺寸的能力为MGBs对蛋白质-DNA相互作用的变构扰动提供了分子基础。本研究揭示了MGBs的作用机制,揭示了其抗肿瘤和抗菌活性的重要结构特征,这对于指导MGB衍生物作为新型抗菌和抗癌药物的未来发展具有重要意义。
Antimicrobial and chemotherapy resistance are escalating medical problem of paramount importance. Yet, research for novel antimicrobial and anticancer agents remains lagging behind. With their reported medical applications, DNA minor groove binders (MGBs) are worthy of exploration. In this study, the approach of structure-based drug design was implemented to generate 11 MGB compounds including a novel class of bioactive alkyne-linked MGBs. The NCI screening protocol was utilized to evaluate the antitumor activity of the target MGBs. Furthermore, a variety of bactericidal, cytopathogenicity, MIC90, and cytotoxicity assays were carried out using these MGBs against 6 medically relevant bacteria: Salmonella enterica, Escherichia coli, Serratia marcescens, Bacillus cereus, Streptococcus pneumoniae and Streptococcus pyogenes. Moreover, molecular docking, molecular dynamic simulations, DNA melting, and isothermal titration calorimetry (ITC) analyses were utilized to explore the binding mode and interactions between the most potent MGBs and the DNA duplex d(CGACTAGTCG)2. NCI results showed that alkyne-linked MGBs (26 & 28) displayed the most significant growth inhibition among the NCI-60 panel. In addition, compounds MGB3, MGB4, MGB28, and MGB32 showed significant bactericidal effects, inhibited B. cereus and S. enterica-mediated cytopathogenicity, and exhibited low cytotoxicity. MGB28 and MGB32 demonstrated significant inhibition of S. pyogenes, whereas MGB28 notably inhibited S. marcescens and all four minor groove binders significantly inhibited B. cereus. The ability of these compounds to bind with DNA and distort its groove dimensions provides the molecular basis for the allosteric perturbation of proteins-DNA interactions by MGBs. This study shed light on the mechanism of action of MGBs and revealed the important structural features for their antitumor and antibacterial activities, which are important to guide future development of MGB derivatives as novel antibacterial and anticancer agents.