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Integrated virtual screening and molecular dynamics simulation revealed promising drug candidates of p53-MDM2 interaction

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Abstract

In the vast majority of malignancies, the p53 tumor suppressor pathway is compromised. In some cancer cells, high levels of MDM2 polyubiquitinate p53 and mark it for destruction, thereby leading to a corresponding downregulation of the protein. MDM2 interacts with p53 via its hydrophobic pocket, and chemical entities that block the dimerization of the protein–protein complex can restore p53 activity. Thus far, only a few chemical compounds have been reported as potent arsenals against p53-MDM2. The Protein Data Bank has crystallogaphic structures of MDM2 in complex with certain compounds. Herein, we have exploited one of the complexes in the identification of new p53-MDM2 antagonists using a hierarchical virtual screening technique. The initial stage was to compile a targeted library of structurally appropriate compounds related to a known effective inhibitor, Nutlin 2, from the PubChem database. The identified 57 compounds were subjected to virtual screening using molecular docking to discover inhibitors with high binding affinity for MDM2. Consequently, five compounds with higher binding affinity than the standard emerged as the most promising therapeutic candidates. When compared to Nutlin 2, four of the drug candidates (CID_140017825, CID_69844501, CID_22721108, and CID_22720965) demonstrated satisfactory pharmacokinetic and pharmacodynamic profiles. Finally, MD simulation of the dynamic behavior of lead-protein complexes reveals the stability of the complexes after a 100,000 ps simulation period. In particular, when compared to the other three leads, overall computational modeling found CID_140017825 to be the best pharmacological candidate. Following thorough experimental trials, it may emerge as a promising chemical entity for cancer therapy.

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Authors and Affiliations

  1. Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomosho, Nigeria

    Abdul-Quddus Kehinde Oyedele, Temitope Isaac Adelusi, Abdeen Tunde Ogunlana, Rofiat Oluwabusola Adeyemi, Opeyemi Emmanuel Atanda & Ibrahim Damilare Boyenle

  2. Department of Biochemistry and Nutrition, Nigerian Institute of Medical Research (NIMR), Yaba, Lagos, Nigeria

    Abdul-Quddus Kehinde Oyedele, Rofiat Oluwabusola Adeyemi & Isong Josiah Ayoola

  3. Department of Biochemistry, University of Lagos, Lagos, Nigeria

    Musa Oladayo Babalola

  4. Department of Chemical Sciences, Biochemistry Unit, College of Natural and Applied Science, Fountain University, Osogbo, Nigeria

    Mojeed Ayoola Ashiru

  5. College of Health Sciences, Crescent University, Abeokuta, Nigeria

    Ibrahim Damilare Boyenle

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  1. Abdul-Quddus Kehinde Oyedele
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  2. Temitope Isaac Adelusi
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  9. Ibrahim Damilare Boyenle
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Contributions

Abdul-Quddus Kehinde Oyedele- conceptualization, writing (original draft), formal analysis, and investigation. Ibrahim Damilare Boyenle- conceptualization, formal analysis, and investigation. Temitope Isaac Adelusi- writing (review and editing). Abdeen Tunde Ogunlana- formal analysis and investigation. Rofiat Oluwabusola Adeyemi- data curation. Opeyemi Emmanuel Atanda- software and visualization. Musa Oladayo Babalola- review and editing. Mojeed Ayoola Ashiru- data curation. Isong Josiah Ayoola- software and visualization.

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Correspondence to Ibrahim Damilare Boyenle.

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Oyedele, AQ.K., Adelusi, T.I., Ogunlana, A.T. et al. Integrated virtual screening and molecular dynamics simulation revealed promising drug candidates of p53-MDM2 interaction. J Mol Model 28, 142 (2022). https://doi.org/10.1007/s00894-022-05131-w

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