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Updated: Feb 15, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Precision screening identifies mitoxantrone as a multitarget inhibitor in ageing-associated cancers with extensive
Mohammed H Al-Qahtani1,2, Mourad Assidi1,2, Abdelbaset Buhmeida1,2
1Institute of Genomic Medicine Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract:
Ageing-associated cancers are characterised by the dual hallmarks of persistent DNA damage and the ability of tumour cells to escape senescence checkpoints, which drive genomic instability and uncontrolled proliferation. In this study, we identified crucial proteins with PDB IDs-2YEX (Chk1 kinase), 4HG7 (MDM2 E3 ubiquitin ligase), 4JSX (mTOR kinase domain), and 5DS3 (PARP-1 DNA repair enzyme)-involved in ageing-related cancers and performed docking studies with Extra Precision (XP) followed by MM-GBSA-based pose processing against the FDA-approved DrugBank library (LigPrep: 10907 compounds). The extensive docking computations identified many good candidates; however, Mitoxantrone emerges as the topmost candidate with docking scores of -6.23 to -16.044 Kcal/mol and MM-GBSA score of -49.19 to -85.14 Kcal/mol, which currently is being used to treat advanced prostate cancer and acute nonlymphocytic leukaemia (ANLL) and would be easier to repurpose to other ageing-related cancers. Mitoxantrone also emerges as a better candidate compared to the control drug Doxorubicin. Further, the complex of all 4 proteins with Mitoxantrone was taken for interaction fingerprints and found that the most interacting residues with counts were 6GLY, 6VAL, 5GLU, 5LEU, 4ALA, 3ASP, and 3TYR, among others. The pharmacokinetics and Density Functional Theory computations further support Mitoxantrone as a potential candidate. We also performed a 5-nanoseconds (ns) WaterMap for hydration site identification and the role of water in stabilisation of the complex, followed by a 100 ns MD Simulation that resulted in stable deviation and fluctuations mostly under <2Å and a web of simulation interactions making the complex stable. Furthermore, the same trajectories were used for the Binding Free and Total Complex Energies computations, revealing that the complexes were stable. All the studies, from protein energies to docking to simulation and binding free energy, supported the stable complexes; however, experimental studies are necessary before their use.
Insights
Mitoxantrone shows promise for repurposing in aging-related cancers by effectively targeting key proteins involved in DNA damage and cell proliferation. This computational study identified it as a superior candidate over Doxorubicin for potential new cancer therapies.
Area of Science:
- Computational drug discovery and repurposing
- Molecular modeling and simulation in oncology
Background:
- Aging-associated cancers exhibit persistent DNA damage and evade senescence, leading to genomic instability and uncontrolled proliferation.
- Key proteins like Chk1 kinase, MDM2 ligase, mTOR kinase, and PARP-1 are implicated in these cancer hallmarks.
Purpose of the Study:
- To identify potential drug candidates for repurposing in aging-related cancers through computational screening.
- To evaluate the efficacy of Mitoxantrone against crucial proteins involved in cancer development and progression.
Main Methods:
- Docking studies (Extra Precision) and MM-GBSA pose processing against the DrugBank library (10,907 compounds).
- Molecular dynamics (MD) simulations (100 ns), WaterMap analysis, and Binding Free Energy computations.
- Pharmacokinetic and Density Functional Theory (DFT) analyses were performed.
Main Results:
- Mitoxantrone emerged as the top candidate, exhibiting strong docking scores (-6.23 to -16.044 Kcal/mol) and MM-GBSA scores (-49.19 to -85.14 Kcal/mol).
- Mitoxantrone demonstrated superior binding affinity compared to the control drug Doxorubicin.
- MD simulations confirmed the stability of Mitoxantrone-protein complexes, with minimal deviation (<2Å) and stable interactions.
Conclusions:
- Mitoxantrone is a highly promising candidate for repurposing in aging-related cancers due to its potent interactions with target proteins.
- Computational findings support Mitoxantrone's stability and efficacy, warranting further experimental validation for therapeutic application.
- This study highlights the potential of computational approaches in identifying novel therapeutic strategies for complex diseases like aging-associated cancers.
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