Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods [version 1; peer review: 2 approved]
Background: Heat shock protein (Hsp90KDa) is a molecular chaperone involved in the process of cellular oncogenesis, hence its importance as a therapeutic target in clinical trials. Geldanamycin is an inhibitor of Hsp90 chaperone activity, which binds to the ATP binding site in the N-terminal domain...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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F1000 Research Ltd
2019-12-01
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| Series: | F1000Research |
| Online Access: | https://f1000research.com/articles/8-2040/v1 |
| _version_ | 1818109075726008320 |
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| author | Ricardo Vivas-Reyes Alejando Morales-Bayuelo Carlos Gueto Juan C. Drosos Johana Márquez Lázaro Rosa Baldiris Maicol Ahumedo Catalina Vivas-Gomez Dilia Aparicio |
| author_facet | Ricardo Vivas-Reyes Alejando Morales-Bayuelo Carlos Gueto Juan C. Drosos Johana Márquez Lázaro Rosa Baldiris Maicol Ahumedo Catalina Vivas-Gomez Dilia Aparicio |
| author_sort | Ricardo Vivas-Reyes |
| collection | DOAJ |
| description | Background: Heat shock protein (Hsp90KDa) is a molecular chaperone involved in the process of cellular oncogenesis, hence its importance as a therapeutic target in clinical trials. Geldanamycin is an inhibitor of Hsp90 chaperone activity, which binds to the ATP binding site in the N-terminal domain of Hsp90. However, geldanamycin has shown hepatotoxic damage in clinical trials; for this reason, its use is not recommended. Taking advantage that geldanamycin binds successfully to Hsp90, many efforts have focused on the search for similar analogues, which have the same or better biological response and reduce the side effects of its predecessor; 17-AAG and 17-DMAG are examples of these analogues. Methods: In order to know the chemical factors influencing the growth or decay of the biological activity of geldanamycin analogues, different computational techniques such as docking, 3DQSAR and quantum similarity were used. Moreover, the study quantified the interaction energy between amino acids residues of active side and geldanamycin analogues, through hybrid methodologies and density functional theory (DFT) indexes. Results: The evaluation of interaction energies showed that the interaction with Lys58 residue is essential for the union of the analogues to the active site of Hsp90, and improves its biological activity. This union is formed through a substituent on C-11 of the geldanamycin macrocycle. A small and attractor group was found as the main steric and electrostatic characteristic that substituents on C11 need in order to interact with Lys 58; behavior was observed with hydroxy and methoxy series of geldanamycin analogues, under study. Conclusion: These outcomes were supported with quantum similarity and reactivity indices calculations using DFT in order to understand the non-covalent stabilization in the active site of these compounds. |
| first_indexed | 2024-12-11T02:25:29Z |
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| institution | Directory Open Access Journal |
| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-12-11T02:25:29Z |
| publishDate | 2019-12-01 |
| publisher | F1000 Research Ltd |
| record_format | Article |
| series | F1000Research |
| spelling | doaj.art-6975abf1dcce4042b315bfc72bcf0a842022-12-22T01:23:56ZengF1000 Research LtdF1000Research2046-14022019-12-01810.12688/f1000research.20844.122924Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods [version 1; peer review: 2 approved]Ricardo Vivas-Reyes0Alejando Morales-Bayuelo1Carlos Gueto2Juan C. Drosos3Johana Márquez Lázaro4Rosa Baldiris5Maicol Ahumedo6Catalina Vivas-Gomez7Dilia Aparicio8Grupo GINUMED, Facultad de Salud, Programa de Medicina, Corporación Universitaria Rafael Núñez, Cartagena, Bolívar, ColombiaGrupo de investigación (CIPTEC), Facultad de Ingeniería, Programa de Ingeniería de Procesos, Fundación Universitaria Tecnológico Comfenalco, Cartagena, Bolívar, ColombiaGrupo de Química Cuántica y Teórica, Programa de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena, Bolívar, ColombiaGrupo de Bioinorganica, Programa de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena, Bolívar, ColombiaGrupo de Química Cuántica y Teórica, Programa de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena, Bolívar, ColombiaGrupo de investigación (CIPTEC), Facultad de Ingeniería, Programa de Ingeniería de Procesos, Fundación Universitaria Tecnológico Comfenalco, Cartagena, Bolívar, ColombiaGrupo de Química Cuántica y Teórica, Programa de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena, Bolívar, ColombiaGrupo de Química Cuántica y Teórica, Programa de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Cartagena, Cartagena, Bolívar, ColombiaGrupo GINUMED, Facultad de Salud, Programa de Medicina, Corporación Universitaria Rafael Núñez, Cartagena, Bolívar, ColombiaBackground: Heat shock protein (Hsp90KDa) is a molecular chaperone involved in the process of cellular oncogenesis, hence its importance as a therapeutic target in clinical trials. Geldanamycin is an inhibitor of Hsp90 chaperone activity, which binds to the ATP binding site in the N-terminal domain of Hsp90. However, geldanamycin has shown hepatotoxic damage in clinical trials; for this reason, its use is not recommended. Taking advantage that geldanamycin binds successfully to Hsp90, many efforts have focused on the search for similar analogues, which have the same or better biological response and reduce the side effects of its predecessor; 17-AAG and 17-DMAG are examples of these analogues. Methods: In order to know the chemical factors influencing the growth or decay of the biological activity of geldanamycin analogues, different computational techniques such as docking, 3DQSAR and quantum similarity were used. Moreover, the study quantified the interaction energy between amino acids residues of active side and geldanamycin analogues, through hybrid methodologies and density functional theory (DFT) indexes. Results: The evaluation of interaction energies showed that the interaction with Lys58 residue is essential for the union of the analogues to the active site of Hsp90, and improves its biological activity. This union is formed through a substituent on C-11 of the geldanamycin macrocycle. A small and attractor group was found as the main steric and electrostatic characteristic that substituents on C11 need in order to interact with Lys 58; behavior was observed with hydroxy and methoxy series of geldanamycin analogues, under study. Conclusion: These outcomes were supported with quantum similarity and reactivity indices calculations using DFT in order to understand the non-covalent stabilization in the active site of these compounds.https://f1000research.com/articles/8-2040/v1 |
| spellingShingle | Ricardo Vivas-Reyes Alejando Morales-Bayuelo Carlos Gueto Juan C. Drosos Johana Márquez Lázaro Rosa Baldiris Maicol Ahumedo Catalina Vivas-Gomez Dilia Aparicio Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods [version 1; peer review: 2 approved] F1000Research |
| title | Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods [version 1; peer review: 2 approved] |
| title_full | Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods [version 1; peer review: 2 approved] |
| title_fullStr | Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods [version 1; peer review: 2 approved] |
| title_full_unstemmed | Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods [version 1; peer review: 2 approved] |
| title_short | Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods [version 1; peer review: 2 approved] |
| title_sort | study of interaction energies between residues of the active site of hsp90 and geldanamycin analogues using quantum mechanics molecular mechanics methods version 1 peer review 2 approved |
| url | https://f1000research.com/articles/8-2040/v1 |
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