Methyllysine reading protein Spindlin 1 (SPIN1) plays a crucial role in histone post-translational modifications and serves as an effective target for the treatment of various malignant tumours. Although several inhibitors targeting SPIN1 expression have been identified, the atomic-level interactions between SPIN1 and inhibitors remain unclear. In this study, six potential SPIN1 inhibitors A366, EML631, MS31, MS8535, vinspinln, and XY49-92B were selected for molecular docking with SPIN1. Conformational changes in SPIN1 induced by these inhibitors, as well as their interactions, were investigated using molecular dynamics simulation (MD) and energy prediction methods including molecular mechanics generalized Born surface area (MM-GBSA) and solvation interaction energy (SIE). The findings indicate that the binding pockets within domain II, specifically Phe141, Trp151, Tyr170, and Tyr177, engage in cation-π interactions with these inhibitors, while also contributing to van der Waals hydrophobic interactions of varying strengths. These van der Waals hydrophobic interactions are critical for their binding affinity, while electrostatic interactions are significantly counterbalanced by polar solvation effects. In addition, through virtual screening and molecular docking, a new lead compound CXY49 was found presenting an effective binding to SPIN1. The structural and energetic changes identified in this study provide valuable insights for the development of new SPIN1 inhibitors.
