Abstract:
The oral pathogen Fusobacterium nucleatum has recently been associated with an elevated risk of colorectal cancer (CRC), endometrial metastasis, chemoresistance, inflammation, metastasis, and DNA damage, along with several other diseases. This study aimed to explore the disruption of protein machinery of F. nucleatum via inhibition of elongation factor thermo unstable (Ef-Tu) protein, through natural products. No study on Ef-Tu inhibition by natural products or in Fusobacterium spp. exists till todate. Ef-Tu is an abundant specialized drug target in bacteria that varies from human Ef-Tu. Elfamycins target Ef-Tu and hence, Enacyloxin IIa was used to generate pharmacophore for virtual screening of three natural product libraries, Natural Product Activity and Species Source (NPASS) (n = 30000 molecules), Tibetan medicinal plant database (n = 54 molecules) and African medicinal plant database (n > 6000 molecules). Peptaibol Septocylindrin B (NPC141050), Hirtusneanoside, and ZINC95486259 were prioritized from these libraries as potential therapeutic candidates. ADMET profiling was done for safety assessment, physiological-based pharmacokinetic modeling in human and mouse for getting insight into drug interaction with body tissues and molecular dynamics was used to assess stability of the best hit NPC141050 (Septocylindrin B). Based on the promising results, we propose further in vitro, in vivo and pharmacokinetic testing on the lead Septocylindrin B, for possible translation into therapeutic interventions.
摘要:
口腔病原体核梭杆菌最近与结直肠癌(CRC)的风险升高有关,子宫内膜转移,化学抗性,炎症,转移,和DNA损伤,还有其他几种疾病。本研究旨在探索通过抑制延伸因子热不稳定(Ef-Tu)蛋白破坏F.通过天然产品。没有研究天然产物或梭杆菌属对Ef-Tu的抑制作用。一直存在到今天。Ef-Tu是细菌中丰富的专门药物靶标,与人类Ef-Tu不同。Elfamycins靶向Ef-Tu,因此,EnacyloxinIIa用于生成药效团,用于三个天然产品库的虚拟筛选,天然产物活性和物种来源(NPASS)(n=30000分子),藏药用植物数据库(n=54分子)和非洲药用植物数据库(n>6000分子)。PeptaibolSeptocylindrinB(NPC141050),Hirtusneanoside,和ZINC95486259从这些文库中优先作为潜在的治疗候选物.进行了ADMET分析以进行安全性评估,在人和小鼠中基于生理学的药代动力学模型,用于深入了解药物与身体组织和分子动力学的相互作用,以评估最佳命中NPC141050(SeptocylindrinB)的稳定性.基于有希望的结果,我们建议在体外进一步,在体内和药代动力学测试铅SeptocylindrinB,可能转化为治疗干预措施。