Structure-based design and biological evaluation of novel mTOR inhibitors as potential anti-cervical agents

The mammalian target of rapamycin(mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches. Herein, we describe the structure-based drug discovery and biological evaluation of a series of m TOR kinase inhibitors as potential anti-cervical cancer agents. The results of enzymatic activity assays supported C3 as a potential m TOR inhibitor, which exhibited high inhibitory activity with an IC50 of 1.57 μM. Molecular docking and dynamics simulation were conducted to predict the binding patterns, suggesting relationships between structure and activity. The anti-proliferative assay against diverse cancer cell lines was displayed subsequently, revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell He La(IC50=0.38μM) compared with other cell lines. Moreover, C3 could effectively reduce the expression of phospho-ribosomal S6 protein(p-S6) in He La cells in a dose-dependent manner. Noteworthily, m TOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously. These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment.

Evaluating reverse docking on general and selective inhibitors: a case study about glide

As a powerful tool for target prediction,reverse docking remains largely unexplored.The objective evaluation of reverse docking software can help us know better about the strength and weakness of these tools,hence guiding us in target prediction.In the present study,we evaluated the target prediction power of Glide(SP)against general inhibitors and selective inhibitors.The results showed that the scoring tendency could be different for each ligand,and overall scoring sampling was necessary for a better understanding of the docking score for a certain protein-ligand pair.Besides,the input conformation of the binding pocket could affect the docking result.Glide(SP)showed a preferable performance on the target prediction of the general inhibitors.However,the accuracy of the target prediction of the selective inhibitors was relatively low,indicating that Glide(SP)might not be capable for this task.The case study about COVID-19 proved that coagulation factor Xa might be a potential target of chloroquine.Therefore,we recommend the further development of reverse docking tools and rectification of inter-target scoring bias.