Computational screening and design of S100B ligand to block S100B–p53 interaction

The binding of S100B to p53 disables the biological function of p53 as a tumor suppressor and thus causes cancer. It is very important to explore the interaction between S100B and p53 and to develop inhibitors to block the interaction in anti-cancer development. In this work, the interaction of S100B to p53 was studied using molecular dynamics (MD) at the atomic level and organic molecules have been identified as potential inhibitors to block the S100B–p53 interaction. It was indicated in the simulations that S100B residues around GLU45 and GLU46 play an important role in the binding of S100B to p53. The three dimensional structure of S100B obtained from S100B–p53 complex (PDB ID: 1DT7) was used as the target protein receptor. Multiple LUDI screenings for S100B ligands were performed using different searching radii 6.23 Å, 7.23 Å, 8.23 Å, 9.23 Å and 10.23 Å with a searching center which was defined as the geometrical center of S100B residues that are within 5 Å from the p53 C-terminal peptide in the complex. Potential organic compounds were screened from the ZINC database using LUDI program implemented in Cerius2 package and evaluated as potential S100B ligands to block the S100B–p53 interaction. The top-scored compounds were selected for binding affinity calculation. The results show that these top-scored ZINC compounds bind in the location where p53 binds and interact with S100B in a similar fashion as p53, and therefore it is expected that they have the potential to block S100B from binding to p53. The ADME and toxicity properties of the potential S100B ligands were also evaluated.