| Titre : | ELUCIDATION OF THE MECHANISM OF RESISTANCE TO 4-HYDROXY TAMOXIFEN IN ESTROGEN RECEPTOR Α Y537S MUTANT AND IDENTIFICATION OF NOVEL INHIBITORS TARGETING ITS DNA BINDING DOMAIN | | Type de document : | thèse | | Auteurs : | BOURICHA EL MEHDI, Auteur | | Année de publication : | 2023 | | Langues : | Anglais (eng) | | Mots-clés : | Breast cancer Estrogen receptor α Y537S mutation DNA Binding Domain
Inhibitors Molecular dynamics Metadynamics Virtual screening Cancer du sein récepteur des œstrogènes α mutation Y537S inhibiteurs du
domaine de liaison à l'ADN dynamique moléculaire métadynamique criblage virtuel :سرطان الثدي،مستقبالت هرمون االستروجينα طفرةY537S مثبطات مجال ربط الحمض
النووي لديناميكا الجزيئية،الميتاديناميكا | | Résumé : | Interest in developing estrogen receptor alpha (ERα) inhibitors with novel mechanism of
action for the treatment of metastatic Erα+ breast cancer is on the rise since the current anti-
estrogens face an acquired resistance to endocrine therapies caused mainly by acquired
mutations in the ligand-binding domain (LBD) of ERα. The Y537S mutation, in particular, is
associated with a higher degree of resistance among all ERα-LBD mutations by causing
constitutive activity of ERα in the absence of ligand and reducing the affinity and sensitivity
of certain antagonists such as 4-hydroxy tamoxifen (4-OHT).
In this thesis, we first aimed to decrypt the mechanism of resistance to 4-OHT in the presence
of Y537S at the atomistic level, in order to determine the key molecular features that drugs
should possess to effectively combat this resistance. In the second part, we aimed to identify
novel anti-ERα inhibitors with new chemical scaffolds, targeting the DNA binding domain
(DBD) instead of the LBD as an alternative mechanism of action.
To decrypt the mechanism of resistance to 4-OHT in the presence of Y537S, we performed a
comparative study for wild-type and Y537S mutant ERα in complex with 4-OHT using
classical molecular dynamics and metadynamics. The findings of this study indicated that
Helix 12 (H12) disruption is a typical allosteric effect of 4-OHT, allowing the receptor to
maintain an antagonistic conformation. The Y537S mutation induces the loss of this effect by
stabilising H12 through the newly formed H-bond between E380 and S537, thereby
strengthening H12 to adopt an agonistic conformation even when 4-OHT is bound.
To identify new hits with new chemical scaffold targeting DBD, we conducted a structure
based virtual screening of DrugBank against the crystal structure of ERα-DBD, followed by
molecular dynamics simulation and MM-GBSA calculation. This allowed us to identify three
molecules (DB03450, DB02593 and DB08001) showing significant stability and strong
interaction with the key amino acids during MD simulation suggesting a potential inhibition
of the target. | | Numéro (Thèse ou Mémoire) : | D0202022 | | Président : | SAILE Rachid | | Directeur : | BRAHIMI Azeddine ; ZOUAIDIA Fouad Co-advisor | | Juge : | KETTANI Anass | | Juge : | El Harti Jaouad ; EL JAOUDI Rachid | | Juge : | BADOU Abdallah ; RAMLI Youssef |
ELUCIDATION OF THE MECHANISM OF RESISTANCE TO 4-HYDROXY TAMOXIFEN IN ESTROGEN RECEPTOR Α Y537S MUTANT AND IDENTIFICATION OF NOVEL INHIBITORS TARGETING ITS DNA BINDING DOMAIN [thèse] / BOURICHA EL MEHDI, Auteur . - 2023. Langues : Anglais ( eng) | Mots-clés : | Breast cancer Estrogen receptor α Y537S mutation DNA Binding Domain
Inhibitors Molecular dynamics Metadynamics Virtual screening Cancer du sein récepteur des œstrogènes α mutation Y537S inhibiteurs du
domaine de liaison à l'ADN dynamique moléculaire métadynamique criblage virtuel :سرطان الثدي،مستقبالت هرمون االستروجينα طفرةY537S مثبطات مجال ربط الحمض
النووي لديناميكا الجزيئية،الميتاديناميكا | | Résumé : | Interest in developing estrogen receptor alpha (ERα) inhibitors with novel mechanism of
action for the treatment of metastatic Erα+ breast cancer is on the rise since the current anti-
estrogens face an acquired resistance to endocrine therapies caused mainly by acquired
mutations in the ligand-binding domain (LBD) of ERα. The Y537S mutation, in particular, is
associated with a higher degree of resistance among all ERα-LBD mutations by causing
constitutive activity of ERα in the absence of ligand and reducing the affinity and sensitivity
of certain antagonists such as 4-hydroxy tamoxifen (4-OHT).
In this thesis, we first aimed to decrypt the mechanism of resistance to 4-OHT in the presence
of Y537S at the atomistic level, in order to determine the key molecular features that drugs
should possess to effectively combat this resistance. In the second part, we aimed to identify
novel anti-ERα inhibitors with new chemical scaffolds, targeting the DNA binding domain
(DBD) instead of the LBD as an alternative mechanism of action.
To decrypt the mechanism of resistance to 4-OHT in the presence of Y537S, we performed a
comparative study for wild-type and Y537S mutant ERα in complex with 4-OHT using
classical molecular dynamics and metadynamics. The findings of this study indicated that
Helix 12 (H12) disruption is a typical allosteric effect of 4-OHT, allowing the receptor to
maintain an antagonistic conformation. The Y537S mutation induces the loss of this effect by
stabilising H12 through the newly formed H-bond between E380 and S537, thereby
strengthening H12 to adopt an agonistic conformation even when 4-OHT is bound.
To identify new hits with new chemical scaffold targeting DBD, we conducted a structure
based virtual screening of DrugBank against the crystal structure of ERα-DBD, followed by
molecular dynamics simulation and MM-GBSA calculation. This allowed us to identify three
molecules (DB03450, DB02593 and DB08001) showing significant stability and strong
interaction with the key amino acids during MD simulation suggesting a potential inhibition
of the target. | | Numéro (Thèse ou Mémoire) : | D0202022 | | Président : | SAILE Rachid | | Directeur : | BRAHIMI Azeddine ; ZOUAIDIA Fouad Co-advisor | | Juge : | KETTANI Anass | | Juge : | El Harti Jaouad ; EL JAOUDI Rachid | | Juge : | BADOU Abdallah ; RAMLI Youssef |
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