Mitoxantrone 2HCl's adroit activity against cervical cancer replication and maintenance proteins: a multitargeted
Mohammed Ageeli Hakami1, Ali Hazazi2, Mishal Olayan Alsulami3
1Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Al-Quwayiyah, Riyadh, Saudi Arabia.
Abstract:
Cervical cancer poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide and resulting in approximately 300,000 deaths yearly, predominantly caused by high-risk human papillomavirus strains (HPV), mainly types 16 and 18. The scenario poses the urgent need of the hour to develop effective treatment strategies that can address the complexity of cervical cancer and multitargeted inhibitor designing that holds promise as it can simultaneously target multiple proteins and pathways involved in its progression and have the potential to enhance treatment efficacy, reduce the likelihood of drug resistance. In this study, we have performed multitargeted molecular docking of FDA-approved drugs against cervical cancer replication and maintenance proteins- Xenopus kinesin-like protein-2 (3KND), cell division cycle protein-20 (4N14), MCM2-histone complex (4UUZ) and MCM6 Minichromosome maintenance (2KLQ) with HTVS, SP and XP algorithms and have obtained the docking and MM\GBSA score ranging from -8.492 to -5.189 Kcal/mol and -58.16 to -39.07 Kcal/mol. Further, the molecular interaction fingerprints identified ALA, THR, SER, ASN, LEU, and ILE were among the most interacted residues, leaning towards hydrophobic and polar amino acids. The pharmacokinetics and DFT of the compound have shown promising results. The complexes were simulated for 100 ns to study the stability by computing the deviation, fluctuations, and intermolecular interactions formed during the simulation. This study produced promising results, satisfying the criteria that Mitoxantrone 2HCl can be a multitargeted inhibitor against cervical cancer proteins-however, experimental validation is a must before human use.
Insights
Cervical cancer, a major global health issue, requires new treatments. This study identified Mitoxantrone 2HCl as a promising multitargeted inhibitor against key cervical cancer proteins, warranting further investigation.
Area of Science:
- Oncology
- Computational Biology
- Drug Discovery
Background:
- Cervical cancer is a leading cause of death in women globally, primarily driven by high-risk human papillomavirus (HPV) types 16 and 18.
- Developing multitargeted inhibitors is crucial for enhancing treatment efficacy and overcoming drug resistance in cervical cancer therapy.
Purpose of the Study:
- To identify FDA-approved drugs as potential multitargeted inhibitors against cervical cancer replication and maintenance proteins.
- To evaluate the binding affinity and molecular interactions of candidate drugs using computational methods.
Main Methods:
- Multitargeted molecular docking of FDA-approved drugs against Xenopus kinesin-like protein-2 (3KND), cell division cycle protein-20 (4N14), MCM2-histone complex (4UUZ), and MCM6 (2KLQ).
- Utilized HTVS, SP, and XP algorithms, followed by MM/GBSA calculations for binding energy estimation.
- Analyzed molecular interaction fingerprints, pharmacokinetics, DFT, and performed 100 ns molecular dynamics simulations for stability assessment.
Main Results:
- Mitoxantrone 2HCl demonstrated significant binding affinity with docking and MM/GBSA scores ranging from -8.492 to -5.189 Kcal/mol and -58.16 to -39.07 Kcal/mol, respectively.
- Key interactions involved hydrophobic and polar amino acids, including ALA, THR, SER, ASN, LEU, and ILE.
- Molecular dynamics simulations indicated stable complex formation, with promising pharmacokinetic and DFT results.
Conclusions:
- Mitoxantrone 2HCl shows potential as a multitargeted inhibitor against critical cervical cancer proteins.
- Further experimental validation is essential to confirm its therapeutic efficacy and safety for human use.
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