In Silico Studies on GCP-Lys-OMe as a Potential 14-3-3σ Homodimer Stabilizer

14-3-3 sigma is a vital negative cell cycle regulator. Its expression is consistently downregulated in many types of cancer through gene promoter hypermethylation or proteasomal degradation. 14-3-3 sigma needs to form a homodimer to be functional, while dimers are less prone to degradation than monomers. This suggests that a homodimer stabilizer may increase the tumor suppressive activities of 14-3-3 sigma. However, no known homodimer stabilizer of 14-3-3 sigma has been reported to date. Therefore, this study attempts to test the potential capability of GCP-Lys-OMe (previously reported to bind at the dimer interface of 14-3-3 zeta isoform), to bind and stabilize the 14-3-3 sigma homodimer. In silico docking of GCP-Lys-OMe on 14-3-3 sigma showed more favorable interaction energy (−9.63 kcal/mole) to the dimer interface than 14-3-3 zeta (−7.73 kcal/mole). Subsequent 100 ns molecular dynamics simulation of the GCP-Lys-OMe/14-3-3 sigma complex revealed a highly stable interaction with an average root-mean-square deviation of 0.39 nm (protein backbone) and 0.77 nm (ligand atoms). More contacts between residues at the homodimer interface and a smaller coverage of conformational space of protein atoms were detected for the bound form than for the apo form. These results suggest that GCP-Lys-OMe is a potential homodimer stabilizer of 14-3-3 sigma.