Title:Exploring Novel PLK1 Inhibitors based on Computational Studies of
2,4-Diarylaminopyrimidine Derivatives
Volume: 21
Issue: 5
Author(s): Honghao Yang, Yilan Zhao, Xiaojiao Zheng, Xiulian Ju, Fengshou Wu, Xiaogang Luo, Qi Sun*Genyan Liu*
Affiliation:
- Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Key Laboratory for Green Chemical Process
of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan,
430205, P.R. China
- Key Laboratory of Novel Biomass-Based Environmental and Energy Materials in Petroleum and
Chemical Industry, Wuhan Institute of Technology, Wuhan, 430205, P.R. China
- Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Key Laboratory for Green Chemical Process
of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan,
430205, P.R. China
- Key Laboratory of Novel Biomass-Based Environmental and Energy Materials in Petroleum and
Chemical Industry, Wuhan Institute of Technology, Wuhan, 430205, P.R. China
Keywords:
PLK1, DAPDs, 3D-QSAR, molecular docking, molecular dynamics simulation, ADME.
Abstract:
Background: Polo-like kinase 1 (PLK1) is an important target for anti-cancer drugs. A series
of novel 2,4-diarylaminopyrimidine derivatives (DAPDs) as PLK1 inhibitors (PLKIs) with remarkable
activities have been reported recently.
Methods: A systemically computational study was performed on these DAPDs, including threedimensional
quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, and
molecular dynamics (MD) simulation.
Results: The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation
parameters. The dockings revealed the binding modes of DAPDs in PLK1 protein, and two key residue,
Cys133 and Phe183, could interact with DAPDs by hydrogen bonds and π-π stacking, which might be
significant for the activity of these PLKIs. Eight compounds with higher predicted activity than the most
active DAPD-compound (16) were designed based on the 3D-QSAR models. These newly designed compounds
also exhibited higher docking scores than compound 16 in the binding pocket of PLK1. The
ADME predictions and MD simulations further indicated that two hit compounds with reasonable pharmacokinetics
properties could stably bind with PLK1 and have the potential to become novel PLKIs.
Conclusion: Two newly designed compounds might have the potential to be novel PLKIs. These results
might provide important information for the design and development of novel PLKIs.