Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jun 24, 2022; 13(6): 496-504
Published online Jun 24, 2022. doi: 10.5306/wjco.v13.i6.496
Molecular docking of DS-3032B, a mouse double minute 2 enzyme antagonist with potential for oncology treatment development
Vítor Hugo Sales da Mota, Fabrício Freire de Melo, Breno Bittencourt de Brito, Filipe Antônio França da Silva, Kádima Nayara Teixeira
Vítor Hugo Sales da Mota, Kádima Nayara Teixeira, Campus Toledo, Universidade Federal do Paraná, Toledo 85.919-899, Paraná, Brazil
Fabrício Freire de Melo, Breno Bittencourt de Brito, Filipe Antônio França da Silva, Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
Author contributions: da Mota VHS, Freire de Melo F, and Teixeira KN contributed to study conceptualization, methodology, validation, and investigation and writing of the original draft; Freire de Melo F contributed to study conceptualization, methodology, and investigation, and manuscript review; de Brito BB and Silva FAFD contributed to study validation, visualization, and formal analysis and manuscript writing, review, and editing; Silva FAFD contributed to study validation, visualization, and formal analysis, manuscript writing, review, and editing, and supervision; Teixeira KN contributed to study conceptualization, methodology, and investigation, original draft writing, and supervision.
Institutional review board statement: This research was carried out in In silico models, not requiring an Institutional Review Board Statement.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Kádima Nayara Teixeira, PhD, Adjunct Professor, Campus Toledo, Universidade Federal do Paraná, Road 182, km 320/321, Toledo 85.919-899, Paraná, Brazil. kadimateixeira@ufpr.br
Received: August 8, 2021
Peer-review started: August 8, 2021
First decision: September 2, 2021
Revised: September 16, 2021
Accepted: May 28, 2022
Article in press: May 28, 2022
Published online: June 24, 2022
Processing time: 317 Days and 10 Hours
Abstract
BACKGROUND

It is known that p53 suppression is an important marker of poor prognosis of cancers, especially in solid tumors of the breast, lung, stomach, and esophagus; liposarcomas, glioblastomas, and leukemias. Because p53 has mouse double minute 2 (MDM2) as its primary negative regulator, this molecular docking study seeks to answer the following hypotheses: Is the interaction between DS-3032B and MDM2 stable enough for this drug to be considered as a promising neoplastic inhibitor?

AIM

To analyze, in silico, the chemical bonds between the antagonist DS-3032B and its binding site in MDM2.

METHODS

For molecular docking simulations, the file containing structures of MDM2 (receptor) and the drug DS-3032B (ligand) were selected. The three-dimensional structure of MDM2 was obtained from Protein Data Bank, and the one for DS-3032B was obtained from PubChem database. The location and dimensions of the Grid box was determined using AutoDock Tools software. In this case, the dimensions of the Grid encompassed the entire receptor. The ligand DS-3032B interacts with the MDM2 receptor in a physiological environment with pH 7.4; thus, to simulate more reliably, its interaction was made with the calculation for the prediction of its protonation state using the MarvinSketch® software. Both ligands, with and without the protonation, were prepared for molecular docking using the AutoDock Tools software. This software detects the torsion points of the drug and calculates the angle of the torsions. Molecular docking simulations were performed using the tools of the AutoDock platform connected to the Vina software. The analyses of the amino acid residues involved in the interactions between the receptor and the ligand as well as the twists of the ligand, atoms involved in the interactions, and type, strength, and length of the interactions were performed using the PyMol software (pymol.org/2) and Discovery Studio from BIOVIA®.

RESULTS

The global alignment indicated crystal structure 5SWK was more suitable for docking simulations by presenting the p53 binding site. The three-dimensional structure 5SWK for MDM2 was selected from Protein Data Bank and the three-dimensional structure of DS-3032B was selected from PubChem (Compound CID: 73297272; Milademetan). After molecular docking simulations, the most stable conformer was selected for both protonated and non-protonated DS-3032B. The interaction between MDM2 and DS-3032B occurs with high affinity; no significant difference was observed in the affinity energies between the MDM2/pronated DS-3032B (-9.9 kcal/mol) and MDM2/non-protonated DS-3032B conformers (-10.0 kcal/mol). Sixteen amino acid residues of MDM2 are involved in chemical bonds with the protonated DS-3032B; these 16 residues of MDM2 belong to the p53 biding site region and provide high affinity to interaction and stability to drug-protein complex.

CONCLUSION

Molecular docking indicated that DS-3032B antagonist binds to the same region of the p53 binding site in the MDM2 with high affinity and stability, and this suggests therapeutic efficiency.

Keywords: DS-3032B; Mouse double minute 2 antagonist; Molecular docking; Tumor suppressor p53

Core Tip: The knowledge, at the molecular level, of the complexes formed by therapeutic drugs and their target in the body are relevant to understand the efficiency of the drug. These data can be provided, with high reliability, by bioinformatics tools, which saves time in relation to in vitro and in vivo analyses. The drug DS-3032B has been a potential candidate for oncogenic treatment in preclinical trials, but clinical studies are scarce. This work shows data on chemical interactions between this drug and its target, mouse double minute 2, that corroborate the preclinical data and demonstrate the stability of the therapeutic complex.