Exploring binding modes of the selected inhibitors to SND1 by all-atom molecular dynamics simulations

Breast cancer is the leading cause of cancer-related deaths in women. Previous studies have indicated that disrupting the interaction between Metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) can inhibit breast cancer development. Understanding the binding mode of small molecule inhibitors with SND1 is of great significance for designing drugs targeting the MTDH-SND1 complex. In this study, we conducted all-atom molecular dynamics (MD) simulations in solution and performed binding energy calculations to gain insights into the binding mechanism of small molecules to SND1. The binding site of SND1 for small molecules is relatively rigid, and the binding of the small molecule and the mutation of key residues have little effect on the conformation of the binding site. SND1 binds more tightly to C26-A6 than to C26-A2, as C26-A2 undergoes a 180° directional change during the simulation process. The key residue mutations have a direct effect on the position and orientation of small molecule in the binding site. The key residues make primary contributions to the binding energy through van der Waals interaction and nonpolar solvation energy, although the contribution from nonpolar solvation is relatively minor. The key residue mutations also affect the formation of hydrogen bonds and ultimately the stability of the small molecule-SND1 complex.Communicated by Ramaswamy H. Sarma.