Author ORCID Identifier
https://orcid.org/0000-0001-8969-6398
Date of Award
Winter 1-16-2026
Document Type
Thesis (Ph.D.)
Department or Program
Chemistry
First Advisor
Paul J. Robustelli
Second Advisor
Dale F. Mierke
Third Advisor
Michael J. Ragusa
Abstract
Intrinsically disordered proteins (IDPs), which lack stable tertiary structures under physiological conditions, are involved in numerous human diseases and represent an important but challenging class of drug targets. The intrinsically disordered transactivation domain of the androgen receptor (AR) is one such target, and several small molecules targeting this domain have entered clinical trials for the treatment of castration-resistant prostate cancer (CRPC). Despite this therapeutic promise, the molecular mechanisms by which these compounds bind to and inhibit the androgen receptor transactivation domain remain poorly understood.
This thesis uses all-atom molecular dynamics (MD) simulations to elucidate the atomistic binding mechanisms of the CRPC drug candidate EPI-002 and the more potent second-generation inhibitor EPI-7170. The simulations show that both compounds bind at the interface of two transiently helical regions within the androgen receptor transactivation domain, promoting the formation of partially folded, collapsed helical states. EPI-7170 exhibits stronger binding than EPI-002, driven by a network of intermolecular interactions that enhance binding affinity and stabilize helical conformations.
Covalent adducts of EPI-002 and EPI-7170 bound to CYS404 of the androgen receptor transactivation domain were also simulated using the Tau-5$\mathrm{_{R2\_R3}}$ fragment. These covalently modified ensembles remain disordered and heterogeneous; however, covalent attachment further shifts the conformational ensemble toward more compact, helical states relative to the corresponding non-covalent complexes.
Experimental studies have shown that the androgen receptor forms transcriptional condensates upon androgen activation and that small-molecule inhibitors such as EPI-002 and 1aa increase the propensity of the androgen receptor to undergo phase separation. To investigate the molecular basis of this behavior, MD simulations of Tau-5$\mathrm{_{R2}}$ dimerization were performed in the presence and absence of these compounds. Both EPI-002 and 1aa enhance the kinetic and thermodynamic stability of androgen receptor dimers, with 1aa promoting substantially more compact and helical dimer conformations.
Together, these results provide atomic-level insight into how small molecules interact with and modulate the disordered androgen receptor transactivation domain. The findings offer a mechanistic rationale for the differential efficacy of androgen receptor inhibitors and suggest general strategies for targeting intrinsically disordered proteins in drug discovery.
Recommended Citation
Zhu, Jiaqi, "Characterizing interactions between the disordered androgen receptor transactivation domain and small molecule drugs" (2026). Dartmouth College Ph.D Dissertations. 454.
https://digitalcommons.dartmouth.edu/dissertations/454
