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Updated: Jun 12, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Structure-based virtual screening discovers novel PKMYT1 inhibitors
Haoyu Zhang1,2,3, Jinyu Yu1,2,3, Ziheng Yang1,2,3
1Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University Shenyang 110016 China medchemzhao@163.com.
Abstract:
PKMYT1, a member of the WEE family, plays a crucial role in the cell cycle by specifically phosphorylating CDK1-CyclinB at Tyr15 and Thr14. Recent investigations have revealed that the amplification of CCNE1 and the inhibition of PKMYT1 kinase collectively result in synthetic lethality, further indicating that PKMYT1 is promising as an effective target for tumor therapy. Existing PKMYT1 inhibitors are mostly derivatives of RP-6306 or pan-inhibitors, limiting their further development. Herein, we conducted virtual screening of a natural product library, and in vitro enzyme experiments demonstrated that EGCG, GCG, and luteolin exhibited potent inhibitory activities with IC50 values of 0.137 μM, 0.159 μM, and 1.5 μM, respectively. Subsequently, analysis of the hit compounds and RP-6306, using different molecular simulation methods, revealed that stable hydrogen bonds with Asp251 and Glu157 in the DFG region were vital for binding to PKMYT1, more so than hydrogen bonds in the hinge and loop regions.
Insights
Natural compounds EGCG, GCG, and luteolin show potent inhibition of PKMYT1 kinase, a promising cancer therapy target. Molecular simulations reveal key binding interactions, guiding future drug development for PKMYT1 inhibitors.
Area of Science:
- Molecular Biology
- Biochemistry
- Pharmacology
Background:
- PKMYT1 (a WEE family member) is critical for cell cycle regulation by phosphorylating CDK1-CyclinB.
- PKMYT1 kinase is a promising therapeutic target in oncology, especially given synthetic lethality observed with CCNE1 amplification.
- Current PKMYT1 inhibitors are limited, necessitating the discovery of novel compounds.
Purpose of the Study:
- To identify novel natural product inhibitors of PKMYT1 kinase.
- To characterize the inhibitory activity and binding mechanisms of identified compounds.
Main Methods:
- Virtual screening of a natural product library.
- In vitro enzyme inhibition assays to determine IC50 values.
- Molecular simulation techniques to analyze compound-protein interactions.
Main Results:
- EGCG, GCG, and luteolin demonstrated potent PKMYT1 inhibition with IC50 values of 0.137 μM, 0.159 μM, and 1.5 μM, respectively.
- Molecular simulations identified crucial hydrogen bonds with Asp251 and Glu157 in the DFG region as vital for binding.
- Binding interactions in the DFG region were found to be more significant than those in the hinge and loop regions.
Conclusions:
- EGCG, GCG, and luteolin are effective PKMYT1 inhibitors with potential for cancer therapy.
- Understanding the binding interactions, particularly in the DFG region, is key for designing next-generation PKMYT1 inhibitors.
- These findings offer a new avenue for developing targeted cancer treatments by inhibiting PKMYT1.
