Molecular dynamics, database screening, density functional and docking studies of novel RAR ligands in cancer chemotherapy Original Research Article

Due to the major challenge which cancer treatment and cure still imposes after many decades to the international scientific community, there is actually considerable interest in new ligands with increased bioactivity. We have focused on the retinoid acid receptor, which is considered an interesting target for drug design. In this work, we have carried out density functional geometry optimizations and different docking procedures. We have performed screening in a large database (hundreds of thousands of molecules which we optimized at the AM1 level) yielding a set of potential bioactive ligands. Two new ligands were selected and optimized at B3LYP/6-31G* level. A flexible docking program was used to investigate the interactions between the receptor and the new ligands. Molecular dynamics were performed in order to investigate the stability of the two ligands as well as the crystallographic RAR ligand inside the RAR active site. We also investigated the stability of all the main protein–ligand contacts. The parameters of the Rule of Five were investigated. The result of this work is compared with a crystallographic ligand of RAR. One of our theoretically bioactive new ligands indicates stronger and more polar and hydrophobic interactions with the receptor.