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Multitargeted inhibitory effect of Mitoxantrone 2HCl on cervical cancer cell cycle regulatory proteins: a multitargeted docking-based MM\GBSA and MD simulation study

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Abstract

Cervical cancer remains a significant global health concern that starts in the cervix, the lower part of the uterus that connects to the vagina and is caused by the human papillomavirus (HPV), necessitating the development of effective multitargeted effective and resistance-proof therapies. In early-stage cervical cancer may not show any symptoms, however, as the cancer progresses, some people may experience- abnormal vaginal bleeding, watery or bloody vaginal discharge, pain in the pelvis or lower back, pain during sex, and frequent and painful urination. In this study, we screened the complete FDA-approved drug library using a multitargeted inhibitory approach against four cervical cancer proteins, namely mitotic arrest deficient -2, DNA polymerase epsilon B-subunit, benzimidazole-related -1, and threonine-protein kinase-1 which crucially plays its role for the in its development process. We employed the HTVS, SP and XP algorithms for efficient filtering and screening that helped to identify Mitoxantrone 2HCl against all of them with docking and MM\GBSA scores ranging from − 11.63 to − 7.802 kcal/mol and − 74.38 to − 47.73 kcal/mol, respectively. We also evaluated the interaction patterns of each complex and the pharmacokinetics properties that helped gain insight into interactions. Subsequently, we performed multiscale MD simulations for 100 ns to understand the dynamic behaviour and stability of the Mitoxantrone 2HCl -protein complexes that revealed the formation of stable drug-protein complexes and provided insights into the molecular interactions that contribute to Mitoxantrone’s inhibitory effects on these proteins and can be a better drug for cervical cancer. However, experimental studies of these findings could pave the way for therapies to combat cervical cancer effectively.

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Acknowledgements

 The authors are thankful to the deanship of scientific research at Najran University for funding this work under the research priorities and Najran research funding program (NU/NRP/MRC/12/8).

Funding

This study was supported by Ministry of Education—Kingdom of Saudi Arabi, NU/NRP/MRC/12/8.

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Authors and Affiliations

  1. Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, P. O. Box 7 1988, Najran, 61441, Saudi Arabia

    Mohammed Ali Alshehri & Saeed Ahmed Asiri

  2. Department of Applied Medical Sciences, Applied College, Al-Baha University, Al-Baha City, Saudi Arabia

    Abdulrahman Alzahrani

  3. Department of Biochemistry, College of Science, University of Jeddah, Jeddah, 23445, Saudi Arabia

    Reem S. Alazragi & Leena S. Alqahtani

  4. Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam, 31441, Saudi Arabia

    Amany I. Alqosaibi & Mashael M. Alnamshan

  5. Molecular Genomics and Precision Department, ExpressMed Diagnostics and Research, Zinj, Kingdom of Bahrain

    Qamre Alam

  6. Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

    Misbahuddin M. Rafeeq

Authors
  1. Mohammed Ali Alshehri
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  2. Saeed Ahmed Asiri
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  3. Abdulrahman Alzahrani
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  4. Reem S. Alazragi
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  6. Amany I. Alqosaibi
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  8. Qamre Alam
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  9. Misbahuddin M. Rafeeq
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Contributions

MAA and SAA: Conceptualisation, Data collection/curation, writing the first draft; QA and AA: Data collection/curation, analysis; RSA and LSA: extensive editing of the first draft; MMR: Supervision, reviewing and editing, AIA; extensive editing of the first draft, MMA: reviewing and editing.

Corresponding author

Correspondence to Misbahuddin M. Rafeeq.

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Alshehri, M.A., Asiri, S.A., Alzahrani, A. et al. Multitargeted inhibitory effect of Mitoxantrone 2HCl on cervical cancer cell cycle regulatory proteins: a multitargeted docking-based MM\GBSA and MD simulation study. Med Oncol 40, 337 (2023). https://doi.org/10.1007/s12032-023-02203-6

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