Understanding the Hsp90 <i>N</i>-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922)
Heat shock protein 90 (Hsp90) is a crucial component in carcinogenesis and serves as a molecular chaperone that facilitates protein maturation whilst protecting cells against temperature-induced stress. The function of Hsp90 is highly dependent on adenosine triphosphate (ATP) binding to the <i>...
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MDPI AG
2020-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/8/1785 |
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| author | Ayanda M. Magwenyane Ndumiso N. Mhlongo Monsurat M. Lawal Daniel G. Amoako Anou M. Somboro Sphelele C. Sosibo Letitia Shunmugam Rene B. Khan Hezekiel M. Kumalo |
| author_facet | Ayanda M. Magwenyane Ndumiso N. Mhlongo Monsurat M. Lawal Daniel G. Amoako Anou M. Somboro Sphelele C. Sosibo Letitia Shunmugam Rene B. Khan Hezekiel M. Kumalo |
| author_sort | Ayanda M. Magwenyane |
| collection | DOAJ |
| description | Heat shock protein 90 (Hsp90) is a crucial component in carcinogenesis and serves as a molecular chaperone that facilitates protein maturation whilst protecting cells against temperature-induced stress. The function of Hsp90 is highly dependent on adenosine triphosphate (ATP) binding to the <i>N</i>-terminal domain of the protein. Thus, inhibition through displacement of ATP by means of competitive binding with a suitable organic molecule is considered an attractive topic in cancer research. Radicicol (RD) and its derivative, resorcinylic isoxazole amine NVP-AUY922 (NVP), have shown promising pharmacodynamics against Hsp90 activity. To date, the underlying binding mechanism of RD and NVP has not yet been investigated. In this study, we provide a comprehensive understanding of the binding mechanism of RD and NVP, from an atomistic perspective. Density functional theory (DFT) calculations enabled the analyses of the compounds’ electronic properties and results obtained proved to be significant in which NVP was predicted to be more favorable with solvation free energy value of −23.3 kcal/mol and highest stability energy of 75.5 kcal/mol for a major atomic delocalization. Molecular dynamic (MD) analysis revealed NVP bound to Hsp90 (NT-NVP) is more stable in comparison to RD (NT-RD). The Hsp90 protein exhibited a greater binding affinity for NT-NVP (−49.4 ± 3.9 kcal/mol) relative to NT-RD (−28.9 ± 4.5 kcal/mol). The key residues influential in this interaction are Gly 97, Asp 93 and Thr 184. These findings provide valuable insights into the Hsp90 dynamics and will serve as a guide for the design of potent novel inhibitors for cancer treatment. |
| first_indexed | 2024-03-10T20:30:27Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T20:30:27Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-dd39f11f5f4e451781cb2b9b520e038d2023-11-19T21:30:58ZengMDPI AGMolecules1420-30492020-04-01258178510.3390/molecules25081785Understanding the Hsp90 <i>N</i>-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922)Ayanda M. Magwenyane0Ndumiso N. Mhlongo1Monsurat M. Lawal2Daniel G. Amoako3Anou M. Somboro4Sphelele C. Sosibo5Letitia Shunmugam6Rene B. Khan7Hezekiel M. Kumalo8Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaSchool of Physical and Chemical Sciences, Department of Chemistry, North West University, Mafikeng Campus, Mmabatho 2790, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaHeat shock protein 90 (Hsp90) is a crucial component in carcinogenesis and serves as a molecular chaperone that facilitates protein maturation whilst protecting cells against temperature-induced stress. The function of Hsp90 is highly dependent on adenosine triphosphate (ATP) binding to the <i>N</i>-terminal domain of the protein. Thus, inhibition through displacement of ATP by means of competitive binding with a suitable organic molecule is considered an attractive topic in cancer research. Radicicol (RD) and its derivative, resorcinylic isoxazole amine NVP-AUY922 (NVP), have shown promising pharmacodynamics against Hsp90 activity. To date, the underlying binding mechanism of RD and NVP has not yet been investigated. In this study, we provide a comprehensive understanding of the binding mechanism of RD and NVP, from an atomistic perspective. Density functional theory (DFT) calculations enabled the analyses of the compounds’ electronic properties and results obtained proved to be significant in which NVP was predicted to be more favorable with solvation free energy value of −23.3 kcal/mol and highest stability energy of 75.5 kcal/mol for a major atomic delocalization. Molecular dynamic (MD) analysis revealed NVP bound to Hsp90 (NT-NVP) is more stable in comparison to RD (NT-RD). The Hsp90 protein exhibited a greater binding affinity for NT-NVP (−49.4 ± 3.9 kcal/mol) relative to NT-RD (−28.9 ± 4.5 kcal/mol). The key residues influential in this interaction are Gly 97, Asp 93 and Thr 184. These findings provide valuable insights into the Hsp90 dynamics and will serve as a guide for the design of potent novel inhibitors for cancer treatment.https://www.mdpi.com/1420-3049/25/8/1785Hsp90 protease<i>N</i>-terminalradicicolNVP-AUY922density functional theory (DFT)molecular dynamics (MD) |
| spellingShingle | Ayanda M. Magwenyane Ndumiso N. Mhlongo Monsurat M. Lawal Daniel G. Amoako Anou M. Somboro Sphelele C. Sosibo Letitia Shunmugam Rene B. Khan Hezekiel M. Kumalo Understanding the Hsp90 <i>N</i>-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922) Molecules Hsp90 protease <i>N</i>-terminal radicicol NVP-AUY922 density functional theory (DFT) molecular dynamics (MD) |
| title | Understanding the Hsp90 <i>N</i>-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922) |
| title_full | Understanding the Hsp90 <i>N</i>-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922) |
| title_fullStr | Understanding the Hsp90 <i>N</i>-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922) |
| title_full_unstemmed | Understanding the Hsp90 <i>N</i>-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922) |
| title_short | Understanding the Hsp90 <i>N</i>-Terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922) |
| title_sort | understanding the hsp90 i n i terminal dynamics structural and molecular insights into the therapeutic activities of anticancer inhibitors radicicol rd and radicicol derivative nvp yua922 |
| topic | Hsp90 protease <i>N</i>-terminal radicicol NVP-AUY922 density functional theory (DFT) molecular dynamics (MD) |
| url | https://www.mdpi.com/1420-3049/25/8/1785 |
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