Identification of natural products as dual sphingosine kinase-1 and programmed cell-death 1-inhibitors by virtual screening and molecular dynamics simulation

Anti-PD-1 have demonstrated significant clinical efficacy in tumor by reversing T-cell dysfunction and exhaustion, therapy enhancing anti-tumoral properties. However, the overall response rate of anti-PD-1 is not high, and responder experience tumor relapse within 2 years. The combination of targeting sphingosine kinase-1 and programmed cell death 1 as a potential therapy way to overcome the problems of immune checkpoint resistance and non-response. Therefore, the primary goal of this study was to discovery natural compounds for dual targeting sphingosine kinase-1 and programmed cell death 1 ligand 1. A natural product database was constructed, and ADMET was used to evaluate natural products for primary screening. Molecular docking and Molecular Mechanics/Generalized Born Surface Area found candidate natural products, three natural products docking conformation were performed 100 ns molecular dynamics simulation. Natural compound 2, 3, 4 have further study value as dual targeting Sphk1 and PD-1 inhibitors.