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Structure-based virtual screening and molecular docking approaches to identify potential inhibitors against KIF2C to
Deema Hussein1,2, Mohamad Saka1,2, Saleh Baeesa3
1King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract:
Glioma, a kind of malignant brain tumor, is extremely lethal. Kinesin family member 2C (KIF2C) was found to have an aberrant expression in several cancer types, including lung cancer and glioma. KIF2C may therefore be a useful therapeutic target for the treatment of glioma. In the current study, new drug candidates that may function as KIF2C enzyme inhibitors were discovered. MTi OpenScreen was used to carry out the structure-based virtual screening of an inbuilt drug library containing 150,000 compounds. These compounds belong to different classes, such as natural product-based compounds (NP-lib), purchasable approved drugs (Drugs-lib), and food constituents compound collection (FOOD-lib). Based on their binding affinities, a total of 84 compounds were further pushed to calculate ADMET properties. The compounds (16) meeting the ADMET cutoff ranges were then further docked to the receptor to find their plausible binding modes using the Glide tool's standard precision (SP) technique. The docking results were examined using the Glide gscore, and the best binding compounds (Rimacalib and Sarizotan) were chosen to test their stability with KIF2C protein through molecular dynamics (MD) simulation. Similarly, Principal Component Analysis and cross-correlation matrix were also examined. The MM/GBSA binding free energies showed a considerable energy contribution in the binding of hits with the KIF2C. Collectively, these findings strongly suggest the potential of the lead compounds to inhibit the biological function of KIF2C, emphasizing the need for further investigation in this area.Communicated by Ramaswamy H. Sarma.
Insights
New drug candidates targeting Kinesin family member 2C (KIF2C) show promise for treating lethal brain tumors like glioma. Structure-based virtual screening identified potent KIF2C inhibitors, including Rimacalib and Sarizotan, warranting further investigation.
Area of Science:
- Oncology
- Biochemistry
- Computational Chemistry
Background:
- Glioma is a highly lethal malignant brain tumor.
- Aberrant expression of Kinesin family member 2C (KIF2C) is observed in cancers, including glioma.
- KIF2C presents a potential therapeutic target for glioma treatment.
Purpose of the Study:
- To discover novel drug candidates that inhibit KIF2C enzyme activity.
- To identify potential therapeutic agents for glioma through structure-based drug design.
Main Methods:
- Structure-based virtual screening of 150,000 compounds using MTi OpenScreen.
- ADMET property prediction and molecular docking (Glide SP) for selected compounds.
- Molecular dynamics (MD) simulations and MM/GBSA binding free energy calculations for lead compounds (Rimacalib, Sarizotan).
Main Results:
- Identified 84 compounds with favorable binding affinities and ADMET properties.
- Docking analysis revealed plausible binding modes for 16 compounds.
- Molecular dynamics simulations and binding energy calculations supported the inhibitory potential of Rimacalib and Sarizotan against KIF2C.
Conclusions:
- The identified lead compounds, Rimacalib and Sarizotan, demonstrate significant potential to inhibit KIF2C's biological function.
- These findings highlight the therapeutic promise of KIF2C inhibitors for glioma treatment.
- Further preclinical investigation of these compounds is recommended.
