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Discovery of potential WEE1 inhibitors via hybrid virtual screening
Tingting Jin1, Wei Xu1, Roufen Chen2
1Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
G2/M cell cycle checkpoint protein WEE1 kinase is a promising target for inhibiting tumor growth. Although various WEE1 inhibitors have entered clinical investigations, their therapeutic efficacy and safety profile remain unsatisfactory. In this study, we employed a comprehensive virtual screening workflow, which included Schrödinger-Glide molecular docking at different precision levels, as well as the utilization of tools such as MM/GBSA and Deepdock to predict the binding affinity between targets and ligands, in order to identify potential WEE1 inhibitors. Out of ten molecules screened, 50% of these molecules exhibited strong inhibitory activity against WEE1. Among them, compounds 4 and 5 showed excellent inhibitory activity with IC50 values of 1.069 and 3.77 nM respectively, which was comparable to AZD1775. Further investigations revealed that compound 4 displayed significant anti-proliferative effects in A549, PC9, and HuH-7 cells and could also induce apoptosis and G1 phase arrest in PC9 cells. Additionally, molecular dynamics simulations unveiled the binding details of compound 4 with WEE1, notably the crucial hydrogen bond interactions formed with Cys379. In summary, this comprehensive virtual screening workflow, combined with in vitro testing and computational modeling, holds significant importance in the development of promising WEE1 inhibitors.
Insights
Researchers identified potent WEE1 kinase inhibitors using virtual screening. Compound 4 demonstrated significant anti-cancer effects and favorable binding interactions, offering a promising avenue for cancer therapy development.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- WEE1 kinase is a key regulator of the G2/M cell cycle checkpoint and a validated target for cancer therapy.
- Existing WEE1 inhibitors show limitations in therapeutic efficacy and safety, necessitating the discovery of novel agents.
Purpose of the Study:
- To identify novel WEE1 kinase inhibitors through a comprehensive virtual screening workflow.
- To evaluate the inhibitory activity, anti-proliferative effects, and binding mechanisms of identified compounds.
Main Methods:
- Virtual screening using Schrödinger-Glide molecular docking, MM/GBSA, and Deepdock.
- In vitro biochemical assays to determine IC50 values.
- Cell-based assays for anti-proliferative effects and cell cycle analysis.
- Molecular dynamics simulations to elucidate binding interactions.
Main Results:
- Ten molecules were screened, with 50% showing strong WEE1 inhibitory activity.
- Compounds 4 and 5 exhibited potent inhibition with IC50 values of 1.069 nM and 3.77 nM, respectively, comparable to AZD1775.
- Compound 4 demonstrated significant anti-proliferative effects in A549, PC9, and HuH-7 cells, inducing apoptosis and G1 phase arrest in PC9 cells.
- Molecular dynamics simulations revealed key hydrogen bond interactions of compound 4 with WEE1, particularly with Cys379.
Conclusions:
- The developed virtual screening workflow is effective for identifying potent WEE1 inhibitors.
- Compound 4 is a promising WEE1 inhibitor with significant anti-cancer potential.
- Further development of identified compounds could lead to improved cancer therapeutics.
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