A selective estrogen receptor (ER) modulator (SERM) therapy is a common hormonal intervention for treating or preventing ER-positive breast cancer. Recent studies have indicated that certain SERMs may also reduce the risk of Alzheimer's. Whether those SERMs can reduce early tau aggregation in the brain is not known. Using molecular modeling and simulations, the tau oligomer disaggregation behaviors of raloxifene, 4-hydroxytamoxifen, and estrogen (control) have been investigated. A self-aggregated and disordered tau-k18 dimer was employed as our tau oligomer model. The 130 residue-long tau-k18 contains the four repeats, representing the well-characterized fibril core of tau from experiments. AutoDock Vina and supervised AI-based SCORCH rescoring of the above SERMs against the tau-k18 dimer, followed by three independent 500ns-long all-atom MD simulations for each docking complex, were performed in explicit solvent and at 310K. The effects of those SERMS on residue-resolved interchain protein interactions were examined using the time- and replicate-averaged residue contact maps. Our results reveal that 4-hydroxytamoxifen has stronger binding to our tau dimer model than raloxifene or estrogen. In addition, a strong site-specific dissociation zone was detected at the N terminal and C terminal of the interacting monomeric tau-k18 chains. Our computational results suggest that certain SERMs may simultaneously inhibit both ER and tau disaggregation and further reveal the dual-targeting potential of SERMs against breast tumors and early Alzheimer's disease.
Cheng et al. (Sun,) studied this question.