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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Research Article

Comparative Dynamic Features of Apo and Bound MDM2 Protein Reveal the Mechanism of Inhibitor Recognition for Anti-Cancer Activity

Author(s): Aisha I. El habbash, Ahmed El Rashedy and Mahmoud E.S. Soliman*

Volume 30, Issue 10, 2023

Published on: 24 October, 2022

Page: [1193 - 1206] Pages: 14

DOI: 10.2174/0929867329666220610194919

Price: $65

Abstract

Background: Mouse Double Minute 2 Homolog (MDM2) oncogenic protein is the principal cellular antagonist of the p53 tumor suppressor gene. Restoration of p53 activity by inhibiting the MDM2-P53 interactions at the molecular level has become the cornerstone of cancer research due to its promising anticancer effects. Natural medicinal products possess various chemical structures and represent an essential source for drug discovery. α-Mangostin (AM) and gambogic acid (G250) are plant-derived compounds that showed inhibitory effects on MDM2-P53 interactions in vitro and in vivo.

Methods: Despite the many clinical studies which performed deeper insight about the molecular understanding of the structural mechanisms exhibited by α-Mangostin and Gambogic acid-binding to MDM2 remains critical. In this study, comparative molecular dynamics simulations were performed for each Apo and bound p53 and MDM2 proteins to shed light on the MDM2-p53 interactions and get a better understanding of the inhibition mechanisms.

Results: Results revealed atomistic interaction of AM and G250 within the MDM2-p53 interaction cleft. Both compounds mediate the interaction between the α-helix motifs of the p53 amino-terminal domain, which caused a significant separation between orthogonally opposed residues, specifically Lys8 and Gly47 residues of the p53 and MDM2, respectively. Contrasting changes in magnitudes were observed in per-residue fluctuation on AM and G250 (~0.04 nm and ~2.3 nm, respectively). The Radius of gyration (~0.03 nm and 0.04 nm, respectively), C-alpha deviations (~0.06 nm and 0.1 nm, respectively). The phenolic group of AM was found to establish hydrogen interactions with Glu28 and His96 residues of MDM2. The trioxahexacyclo-ring of G250 also forms hydrogen bond interactions with Lys51 and Leu26 residues of MDM2.

Conclusion: Utilizing the information provided on the inhibitory binding mode adopted by each compound in this study may further assist in the tailored designs for cancer therapeutics.

Keywords: MDM2, p53, α-mangostin (AM), gambogic acid (G250), anti-cancer, dynamics simulations

« Previous
[1]
Al-Harbi, L.N.; Subash-Babu, P.; Binobead, M.A.; Alhussain, M.H.; AlSedairy, S.A.; Aloud, A.A.; Alshatwi, A.A. Potential metabolite nymphayol isolated from water lily (Nymphaea stellata) flower inhibits MCF-7 human breast cancer cell growth via upregulation of CDKN2A, pRb2, p53 and Downregulation of PCNA mRNA Expressions. Metabolites, 2020, 10(7), 280.
[http://dx.doi.org/10.3390/metabo10070280] [PMID: 32650545]
[2]
Vousden, K.H.; Prives, C. Blinded by the light: The growing complexity of p53. Cell, 2009, 137(3), 413-431.
[http://dx.doi.org/10.1016/j.cell.2009.04.037] [PMID: 19410540]
[3]
Xu, X.H.; Liu, Q.Y.; Li, T.; Liu, J.L.; Chen, X.; Huang, L.; Qiang, W.A.; Chen, X.; Wang, Y.; Lin, L.G.; Lu, J.J. Garcinone E induces apoptosis and inhibits migration and invasion in ovarian cancer cells. Sci. Rep., 2017, 7(1), 10718.
[http://dx.doi.org/10.1038/s41598-017-11417-4] [PMID: 28878295]
[4]
Wang, W.; Hu, Y. Small molecule agents targeting the p53-MDM2 pathway for cancer therapy. Med. Res. Rev., 2012, 32(6), 1159-1196.
[http://dx.doi.org/10.1002/med.20236] [PMID: 23059763]
[5]
Moll, U.M.; Petrenko, O. The MDM2-p53 interaction. Mol. Cancer Res., 2003, 1(14), 1001-1008.
[PMID: 14707283]
[6]
Kussie, P. H.; Gorina, S.; Marechal, V.; Elenbaas, B.; Moreau, J.; Levine, A. J.; Pavletich, N. P. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science, 1996, 274(5289), 948-953.
[http://dx.doi.org/10.1126/science.274.5289.948]
[7]
Fu, T.; Min, H.; Xu, Y.; Chen, J.; Li, G. Molecular dynamic simulation insights into the normal state and restoration of p53 function. Int. J. Mol. Sci., 2012, 13(8), 9709-9740.
[http://dx.doi.org/10.3390/ijms13089709] [PMID: 22949826]
[8]
Pedraza-Chaverri, J.; Cárdenas-Rodríguez, N.; Orozco-Ibarra, M.; Pérez-Rojas, J.M. Medicinal properties of mangosteen (Garcinia mangostana). Food Chem. Toxicol., 2008, 46(10), 3227-3239.
[http://dx.doi.org/10.1016/j.fct.2008.07.024] [PMID: 18725264]
[9]
Chantarasriwong, O.; Batova, A.; Chavasiri, W.; Theodorakis, E.A. Chemistry and biology of the caged Garcinia xanthones. Chemistry, 2010, 16(33), 9944-9962.
[http://dx.doi.org/10.1002/chem.201000741] [PMID: 20648491]
[10]
Chitchumroonchokchai, C.; Thomas-Ahner, J.M.; Li, J.; Riedl, K.M.; Nontakham, J.; Suksumrarn, S.; Clinton, S.K.; Kinghorn, A.D.; Failla, M.L. Anti-tumorigenicity of dietary α-mangostin in an HT-29 colon cell xenograft model and the tissue distribution of xanthones and their phase II metabolites. Mol. Nutr. Food Res., 2013, 57(2), 203-211.
[http://dx.doi.org/10.1002/mnfr.201200539] [PMID: 23239542]
[11]
Zhao, J.; Qi, Q.; Yang, Y.; Gu, H-Y.; Lu, N.; Liu, W.; Wang, W.; Qiang, L.; Zhang, L-B.; You, Q-D.; Guo, Q-L. Inhibition of alpha(4) integrin mediated adhesion was involved in the reduction of B16-F10 melanoma cells lung colonization in C57BL/6 mice treated with gambogic acid. Eur. J. Pharmacol., 2008, 589(1-3), 127-131.
[http://dx.doi.org/10.1016/j.ejphar.2008.04.063] [PMID: 18539272]
[12]
Lemos, A.; Gomes, A.S.; Loureiro, J.B.; Brandão, P.; Palmeira, A.; Pinto, M.M.M.; Saraiva, L.; Sousa, M.E. Synthesis, biological evaluation, and in silico studies of novel aminated xanthones as potential p53-activating agents. Molecules, 2019, 24(10), E1975.
[http://dx.doi.org/10.3390/molecules24101975] [PMID: 31121972]
[13]
Liu, J.; Zhang, J.; Wang, H.; Liu, Z.; Zhang, C.; Jiang, Z.; Chen, H. Synthesis of xanthone derivatives and studies on the inhibition against cancer cells growth and synergistic combinations of them. Eur. J. Med. Chem., 2017, 133, 50-61.
[http://dx.doi.org/10.1016/j.ejmech.2017.03.068] [PMID: 28376372]
[14]
Kaomongkolgit, R.; Chaisomboon, N.; Pavasant, P. Apoptotic effect of alpha-mangostin on head and neck squamous carcinoma cells. Arch. Oral Biol., 2011, 56(5), 483-490.
[http://dx.doi.org/10.1016/j.archoralbio.2010.10.023] [PMID: 21106189]
[15]
Gu, H.; Wang, X.; Rao, S.; Wang, J.; Zhao, J.; Ren, F.L.; Mu, R.; Yang, Y.; Qi, Q.; Liu, W.; Lu, N.; Ling, H.; You, Q.; Guo, Q. Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of MDM2 in wild-type p53-expressing cancer cells. Mol. Cancer Ther., 2008, 7(10), 3298-3305.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0212] [PMID: 18852133]
[16]
Leão, M.; Gomes, S.; Pedraza-Chaverri, J.; Machado, N.; Sousa, E.; Pinto, M.; Inga, A.; Pereira, C.; Saraiva, L. Α-mangostin and gambogic acid as potential inhibitors of the p53-MDM2 interaction revealed by a yeast approach. J. Nat. Prod., 2013, 76(4), 774-778.
[http://dx.doi.org/10.1021/np400049j] [PMID: 23540934]
[17]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[18]
Webb, B.; Sali, A. Protein structure modeling with modeller. In: Protein Structure Prediction. Methods in Molecular Biology (Methods and Protocols); Humana Press: New York, NY, 2014; p. 1137.
[http://dx.doi.org/10.1007/978-1-4939-0366-5_1]
[19]
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A.; Wang, J.; Yu, B.; Zhang, J.; Bryant, S.H. PubChem substance and compound databases. Nucleic Acids Res., 2016, 44(D1), D1202-D1213.
[http://dx.doi.org/10.1093/nar/gkv951] [PMID: 26400175]
[20]
Hospital, A.; Goñi, J.R.; Orozco, M.; Gelpí, J.L. Molecular dynamics simulations: Advances and applications. Adv. Appl. Bioinform. Chem., 2015, 8, 37-47.
[http://dx.doi.org/10.2147/AABC.S70333] [PMID: 26604800]
[21]
Lee, T-S.; Cerutti, D.S.; Mermelstein, D.; Lin, C.; LeGrand, S.; Giese, T.J.; Roitberg, A.; Case, D.A.; Walker, R.C.; York, D.M. GPU-accelerated molecular dynamics and free energy methods in amber18: Performance enhancements and new features. J. Chem. Inf. Model., 2018, 58(10), 2043-2050.
[http://dx.doi.org/10.1021/acs.jcim.8b00462] [PMID: 30199633]
[22]
Wang, J.; Wang, W.; Kollman, P.A.; Case, D.A. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model., 2006, 25(2), 247-260.
[http://dx.doi.org/10.1016/j.jmgm.2005.12.005] [PMID: 16458552]
[23]
Berendsen, H.J.C.; Postma, J.P.M.; van Gunsteren, W.F.; DiNola, A.; Haak, J.R. Molecular dynamics with coupling to an external bath. J. Chem. Phys., 1984, 81(8), 3684.
[http://dx.doi.org/10.1063/1.448118]
[24]
Bakan, A.; Meireles, L.M.; Bahar, I. ProDy: Protein dynamics inferred from theory and experiments. Bioinformatics, 2011, 27(11), 1575-1577.
[http://dx.doi.org/10.1093/bioinformatics/btr168] [PMID: 21471012]
[25]
Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph., 1996, 14(1), 33-38.
[http://dx.doi.org/10.1016/0263-7855(96)00018-5] [PMID: 8744570]
[26]
Roe, D.R.; Cheatham, T.E., III PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput., 2013, 9(7), 3084-3095.
[http://dx.doi.org/10.1021/ct400341p] [PMID: 26583988]
[27]
Seifert, E. OriginPro 9.1: Scientific data analysis and graphing software-software review. J. Chem. Inf. Model., 2014, 54(5), 1552.
[http://dx.doi.org/10.1021/ci500161d] [PMID: 24702057]
[28]
Genheden, S.; Ryde, U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin. Drug Discov., 2015, 10(5), 449-461.
[http://dx.doi.org/10.1517/17460441.2015.1032936] [PMID: 25835573]
[29]
Drissi, M.; Benhalima, N.; Megrouss, Y.; Rachida, R.; Chouaih, A.; Hamzaoui, F. Theoretical and experimental electrostatic potential around the m-nitrophenol molecule. Molecules, 2015, 20(3), 4042-4054.
[http://dx.doi.org/10.3390/molecules20034042] [PMID: 25741898]
[30]
M., J.; Archontis, G. MM-GB(PB)SA Calculations of Protein-Ligand Binding Free Energies. In: Molecular Dynamics - Studies of Synthetic and Biological Macromolecules; InTech, 2012.
[http://dx.doi.org/10.5772/37107]
[31]
Hou, T.; Wang, J.; Li, Y.; Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J. Chem. Inf. Model., 2011, 51(1), 69-82.
[http://dx.doi.org/10.1021/ci100275a] [PMID: 21117705]
[32]
Sitkoff, D.; Sharp, K.A.; Honig, B. Accurate calculation of hydration free energies using macroscopic solvent models. J. Phys. Chem., 1994, 98(7), 43.
[http://dx.doi.org/10.1021/j100058a043]
[33]
Li, M-H.; Luo, Q.; Xue, X-G.; Li, Z-S. Molecular dynamics studies of the 3D structure and planar ligand binding of a quadruplex dimer. J. Mol. Model., 2011, 17(3), 515-526.
[http://dx.doi.org/10.1007/s00894-010-0746-0] [PMID: 20508957]
[34]
Ali, S.A.; Hassan, M.I.; Islam, A.; Ahmad, F. A review of methods available to estimate solvent-accessible surface areas of soluble proteins in the folded and unfolded states. Curr. Protein Pept. Sci., 2014, 15(5), 456-476.
[http://dx.doi.org/10.2174/1389203715666140327114232] [PMID: 24678666]
[35]
Richmond, T.J. Solvent accessible surface area and excluded volume in proteins. Analytical equations for overlapping spheres and implications for the hydrophobic effect. J. Mol. Biol., 1984, 178(1), 63-89.
[http://dx.doi.org/10.1016/0022-2836(84)90231-6] [PMID: 6548264]
[36]
Cournia, Z.; Allen, B.; Sherman, W. Relative binding free energy calculations in drug discovery: Recent advances and practical considerations. J. Chem. Inf. Model., 2017, 57(12), 2911-2937.
[http://dx.doi.org/10.1021/acs.jcim.7b00564] [PMID: 29243483]
[37]
El Habbash, A.I.; Mohd Hashim, N.; Ibrahim, M.Y.; Yahayu, M.; Omer, F.A.E.; Abd Rahman, M.; Nordin, N.; Lian, G.E.C. In vitro assessment of anti-proliferative effect induced by α-mangostin from Cratoxylum arborescens on HeLa cells. PeerJ, 2017, 5(7), e3460.
[http://dx.doi.org/10.7717/peerj.3460] [PMID: 28740747]
[38]
Li, C.; Qi, Q.; Lu, N.; Dai, Q.; Li, F.; Wang, X.; You, Q.; Guo, Q. Gambogic acid promotes apoptosis and resistance to metastatic potential in MDA-MB-231 human breast carcinoma cells. Biochem. Cell Biol., 2012, 90(6), 718-730.
[http://dx.doi.org/10.1139/o2012-030] [PMID: 23194187]
[39]
Shehu, A.; Kavraki, L.E. Modeling structures and motions of loops in protein molecules. Entropy (Basel), 2012, 2012, e14020252.
[http://dx.doi.org/10.3390/e14020252]

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