Lomitapide as a Potential Estrogen Receptor Inhibitor: A Computational Drug Repurposing Study

Zekeriya Düzgün; Funda Demırtaş Korkmaz

Article Details

Lomitapide as a Potential Estrogen Receptor Inhibitor: A Computational Drug Repurposing Study

Authors:

Zekeriya Düzgün | Funda Demırtaş Korkmaz

Publisher:

Kocaeli University

Main Topics:

Biyoinformatik ve Hesaplamalı Biyoloji (Diğer)

Journal:

Kocaeli Üniversitesi Sağlık Bilimleri Dergisi Vol.10 Issue 1, pp.8-14

Document Type:

Article

Publication Date:

3/2024

Document Language:

English

Document ID (Org No.):

2001313284

pISSN:

2149-8571

Keywords:

Abstract:

 Objective: Estrogen receptor ER inhibitors have significant therapeutic potential for hormone-dependent cancers and related disorders. Tamoxifen, a well-known selective estrogen receptor modulator, has been widely used as adjuvant therapy for estrogen receptor-positive breast cancer. However, tamoxifen may exhibit a tendency to develop resistance with prolonged usage and particularly elevate the risk of uterine cancer. Therefore, there is a need for the discovery and development of new ER modulators or inhibitors. In this study, we identified potential estrogen receptor inhibitors through computational drug repositioning. Methods: A set of 2048 compounds, encompassing FDA-approved drugs and active metabolites, were subjected to molecular docking, molecular dynamics simulations, and free energy calculations to evaluate their interaction with estrogen receptor α ERα. Results: Among the compounds evaluated, conivaptan, atogepant, and lomitapide exhibited the highest affinities for ERα. Lomitapide displayed a superior docking score -12 kcalmol compared to the established ER inhibitor, tamoxifen -10 kcalmol. Further investigation using molecular dynamics simulations and free energy calculations disclosed lomitapides heightened binding affinity of -380.727 kJmol, surpassing tamoxifens binding affinity of -352.029 kJmol. Conclusion: This comprehensive computational exploration underscores lomitapides potential as a compelling candidate with an envisaged stronger estrogen receptor affinity than the acknowledged standard, tamoxifen. To validate lomitapides promise as a novel ER inhibitor, essential in vitro and in vivo studies are suggested. These investigations will provide essential insights into lomitapides reposition in addressing the challenges tied to hormone-dependent cancers and associated maladies.

 Objective: Estrogen receptor ER inhibitors have significant therapeutic potential for hormone-dependent cancers and related disorders. Tamoxifen, a well-known selective estrogen receptor modulator, has been widely used as adjuvant therapy for estrogen receptor-positive breast cancer. However, tamoxifen may exhibit a tendency to develop resistance with prolonged usage and particularly elevate the risk of uterine cancer. Therefore, there is a need for the discovery and development of new ER modulators or inhibitors. In this study, we identified potential estrogen receptor inhibitors through computational drug repositioning. Methods: A set of 2048 compounds, encompassing FDA-approved drugs and active metabolites, were subjected to molecular docking, molecular dynamics simulations, and free energy calculations to evaluate their interaction with estrogen receptor α ERα. Results: Among the compounds evaluated, conivaptan, atogepant, and lomitapide exhibited the highest affinities for ERα. Lomitapide displayed a superior docking score -12 kcalmol compared to the established ER inhibitor, tamoxifen -10 kcalmol. Further investigation using molecular dynamics simulations and free energy calculations disclosed lomitapides heightened binding affinity of -380.727 kJmol, surpassing tamoxifens binding affinity of -352.029 kJmol. Conclusion: This comprehensive computational exploration underscores lomitapides potential as a compelling candidate with an envisaged stronger estrogen receptor affinity than the acknowledged standard, tamoxifen. To validate lomitapides promise as a novel ER inhibitor, essential in vitro and in vivo studies are suggested. These investigations will provide essential insights into lomitapides reposition in addressing the challenges tied to hormone-dependent cancers and associated maladies.

 Objective: Estrogen receptor ER inhibitors have significant therapeutic potential for hormone-dependent cancers and related disorders. Tamoxifen, a well-known selective estrogen receptor modulator, has been widely used as adjuvant therapy for estrogen receptor-positive breast cancer. However, tamoxifen may exhibit a tendency to develop resistance with prolonged usage and particularly elevate the risk of uterine cancer. Therefore, there is a need for the discovery and development of new ER modulators or inhibitors. In this study, we identified potential estrogen receptor inhibitors through computational drug repositioning. Methods: A set of 2048 compounds, encompassing FDA-approved drugs and active metabolites, were subjected to molecular docking, molecular dynamics simulations, and free energy calculations to evaluate their interaction with estrogen receptor α ERα. Results: Among the compounds evaluated, conivaptan, atogepant, and lomitapide exhibited the highest affinities for ERα. Lomitapide displayed a superior docking score -12 kcalmol compared to the established ER inhibitor, tamoxifen -10 kcalmol. Further investigation using molecular dynamics simulations and free energy calculations disclosed lomitapides heightened binding affinity of -380.727 kJmol, surpassing tamoxifens binding affinity of -352.029 kJmol. Conclusion: This comprehensive computational exploration underscores lomitapides potential as a compelling candidate with an envisaged stronger estrogen receptor affinity than the acknowledged standard, tamoxifen. To validate lomitapides promise as a novel ER inhibitor, essential in vitro and in vivo studies are suggested. These investigations will provide essential insights into lomitapides reposition in addressing the challenges tied to hormone-dependent cancers and associated maladies.

 Objective: Estrogen receptor ER inhibitors have significant therapeutic potential for hormone-dependent cancers and related disorders. Tamoxifen, a well-known selective estrogen receptor modulator, has been widely used as adjuvant therapy for estrogen receptor-positive breast cancer. However, tamoxifen may exhibit a tendency to develop resistance with prolonged usage and particularly elevate the risk of uterine cancer. Therefore, there is a need for the discovery and development of new ER modulators or inhibitors. In this study, we identified potential estrogen receptor inhibitors through computational drug repositioning. Methods: A set of 2048 compounds, encompassing FDA-approved drugs and active metabolites, were subjected to molecular docking, molecular dynamics simulations, and free energy calculations to evaluate their interaction with estrogen receptor α ERα. Results: Among the compounds evaluated, conivaptan, atogepant, and lomitapide exhibited the highest affinities for ERα. Lomitapide displayed a superior docking score -12 kcalmol compared to the established ER inhibitor, tamoxifen -10 kcalmol. Further investigation using molecular dynamics simulations and free energy calculations disclosed lomitapides heightened binding affinity of -380.727 kJmol, surpassing tamoxifens binding affinity of -352.029 kJmol. Conclusion: This comprehensive computational exploration underscores lomitapides potential as a compelling candidate with an envisaged stronger estrogen receptor affinity than the acknowledged standard, tamoxifen. To validate lomitapides promise as a novel ER inhibitor, essential in vitro and in vivo studies are suggested. These investigations will provide essential insights into lomitapides reposition in addressing the challenges tied to hormone-dependent cancers and associated maladies.

Article Details

Lomitapide as a Potential Estrogen Receptor Inhibitor: A Computational Drug Repurposing Study

Authors:

Zekeriya Düzgün | Funda Demırtaş Korkmaz

Publisher:

Kocaeli University

Main Topics:

Biyoinformatik ve Hesaplamalı Biyoloji (Diğer)

Journal:

Kocaeli Üniversitesi Sağlık Bilimleri Dergisi Vol.10 Issue 1, pp.8-14

Document Type:

Article

Publication Date:

3/2024

Document Language:

English

Document ID (Org No.):

2001313284

pISSN:

2149-8571

Estrogen Receptor Antagonists

Drug Repositioning

Lomitapide

Tamoxifen

Molecular Docking

Molecular Dynamics Simulation

Issues

Article Details

Lomitapide as a Potential Estrogen Receptor Inhibitor: A Computational Drug Repurposing Study

Authors: Zekeriya Düzgün | Funda Demırtaş Korkmaz

Publisher: Kocaeli University

Main Topics: Biyoinformatik ve Hesaplamalı Biyoloji (Diğer)

Journal: Kocaeli Üniversitesi Sağlık Bilimleri Dergisi Vol.10 Issue 1, pp.8-14

Document Type: Article

Publication Date: 3/2024

Document Language: English

Document ID (Org No.): 2001313284

pISSN: 2149-8571

Estrogen Receptor Antagonists

Drug Repositioning

Lomitapide

Tamoxifen

Molecular Docking

Molecular Dynamics Simulation

Issues

Authors:

Zekeriya Düzgün | Funda Demırtaş Korkmaz

Publisher:

Kocaeli University

Main Topics:

Biyoinformatik ve Hesaplamalı Biyoloji (Diğer)

Journal:

Kocaeli Üniversitesi Sağlık Bilimleri Dergisi Vol.10 Issue 1, pp.8-14

Document Type:

Article

Publication Date:

3/2024

Document Language:

English

Document ID (Org No.):

2001313284

pISSN:

2149-8571