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Discovery of Novel Anti-Resistance AR Antagonists Guided by Funnel Metadynamics Simulation.
- Source :
-
Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 May; Vol. 11 (19), pp. e2309261. Date of Electronic Publication: 2024 Mar 13. - Publication Year :
- 2024
-
Abstract
- Androgen receptor (AR) antagonists are widely used for the treatment of prostate cancer (PCa), but their therapeutic efficacy is usually compromised by the rapid emergence of drug resistance. However, the lack of the detailed interaction between AR and its antagonists poses a major obstacle to the design of novel AR antagonists. Here, funnel metadynamics is employed to elucidate the inherent regulation mechanisms of three AR antagonists (hydroxyflutamide, enzalutamide, and darolutamide) on AR. For the first time it is observed that the binding of antagonists significantly disturbed the C-terminus of AR helix-11, thereby disrupting the specific internal hydrophobic contacts of AR-LBD and correspondingly the communication between AR ligand binding pocket (AR-LBP), activation function 2 (AF2), and binding function 3 (BF3). The subsequent bioassays verified the necessity of the hydrophobic contacts for AR function. Furthermore, it is found that darolutamide, a newly approved AR antagonist capable of fighting almost all reported drug resistant AR mutants, can induce antagonistic binding structure. Subsequently, docking-based virtual screening toward the dominant binding conformation of AR for darolutamide is conducted, and three novel AR antagonists with favorable binding affinity and strong capability to combat drug resistance are identified by in vitro bioassays. This work provides a novel rational strategy for the development of anti-resistant AR antagonists.<br /> (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
- Subjects :
- Humans
Phenylthiohydantoin pharmacology
Phenylthiohydantoin analogs & derivatives
Male
Receptors, Androgen metabolism
Receptors, Androgen chemistry
Receptors, Androgen genetics
Nitriles pharmacology
Molecular Dynamics Simulation
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Prostatic Neoplasms drug therapy
Prostatic Neoplasms genetics
Pyrazoles pharmacology
Pyrazoles chemistry
Molecular Docking Simulation methods
Amides pharmacology
Amides chemistry
Flutamide analogs & derivatives
Androgen Receptor Antagonists pharmacology
Androgen Receptor Antagonists chemistry
Benzamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2198-3844
- Volume :
- 11
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Advanced science (Weinheim, Baden-Wurttemberg, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 38481034
- Full Text :
- https://doi.org/10.1002/advs.202309261