Identification of PLK1-PBD Inhibitors from the Library of Marine Natural Products: 3D QSAR Pharmacophore, ADMET, Scaffold Hopping, Molecular Docking, and Molecular Dynamics Study

Abstract

PLK1 is found to be highly expressed in various types of cancers, but the development of inhibitors for it has been slow. Most inhibitors are still in clinical stages, and many lack the necessary selectivity and anti-tumor effects. This study aimed to create new inhibitors for the PLK1-PBD by focusing on the PBD binding domain, which has the potential for greater selectivity. A 3D QSAR model was developed using a dataset of 112 compounds to evaluate 500 molecules. ADMET prediction was then used to select three molecules with strong drug-like characteristics. Scaffold hopping was employed to reconstruct 98 new compounds with improved drug-like properties and increased activity. Molecular docking was used to compare the efficient compound abbapolin, confirming the high-activity status of [(14S)-14-hydroxy-14-(pyridin-2-yl)tetradecyl]ammonium,[(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium. Molecular dynamics simulations and MMPBSA were conducted to evaluate the stability of the compounds in the presence of proteins. An in-depth analysis of [(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium identified them as potential candidates for PLK1 inhibitors.

TRAF6 Inhibitors from Marine Compound Library: Pharmacophore, Virtual Screening, Fragment Replacement, ADMET, and Molecular Dynamics

“…Recent studies have shown that 170 marine compounds and their synthetic analogues have strong anti-cancer biological activity [ 24 , 25 ]. In our previous study, we successfully screened the target PD-L1, CDK4/6, and USP7-targeted inhibitors from the marine active compound library for the treatment and prevention of tumors [ 26 , 27 , 28 , 29 ]. Based on the broad potential of the marine compound library and our previous experience, it is possible to use marine natural compounds to screen potential inhibitors of TRAF6.…”