Virtual Screening of PEBP1 Inhibitors By Combining 2D/3D-QSAR Analysis, Hologram QSAR, Homology Modeling, Molecular Docking Analysis and Molecular Dynamic Simulations

Abstract

\n Human Phosphatidylethanolamine Binding Protein 1 (hPEBP1) is a novel target affecting numerous cellular signaling pathways involving in the formation of metastases. It can be used in the treatment of many cases of cancer. For these reasons, the Pharmaceutical Companies use computational approaches, including Multi-QSAR (2D, 3D, and Hologram QSAR) analysis, Homology modeling and molecular docking analysis and molecular dynamic simulations to accelerate the drug discovery process. In this paper, QSAR modeling was conducted using two quantum chemistry optimization methods (AM1 and DFT levels). As per PLS results, we found that DFT (B3LYP(d, p)) method present high predictability according to 2D-QSAR, CoMFA, CoMSIA, and Hologram QSAR studies, with Q2 of 0.81, 0.67, 0.79 and 0.67 respectively, and external power with R2pred of 0.78, 0.58, 0.66 and 0.56, respectively. This results has been validated by CoMFA/CoMSIA graphics, which suggests that electrostatic fields combined with hydrogen bond donor/acceptor fields are beneficial to the antiproliferative activity. While the Hologram QSAR models show the contributions of each fragment in improving the activity. The results from QSAR analyses revealed that Ursolic Acids with heterocyclic ring could improve the activities. However, Ramachandran plot validated the modeled PEBP1 protein. Whereas, molecular docking and MDs simulations revealed that the hydrophobic and hydrogen bond interactions are dominant in the PEBP1 s pocket. These results, were used to predict the structures of three new compounds with high anticancer activity In Silico, Similarly, molecular docking stability studies and molecular dynamics simulations were conducted.