Hot-Spot Residue-Based Virtual Screening of Novel Selective Estrogen-Receptor Degraders for Breast Cancer Treatment

The estrogen-receptor alfa (ER alpha) is considered pivotal for breast cancer treatment. Although selective estrogen-receptor degraders (SERDs) have been developed to induce ER alpha degradation and antagonism, their agonistic effect on the uterine tissue and poor pharmacokinetic properties limit further application of ER alpha; thus, discovering novel SERDs is necessary. The ligand preferentially interacts with several key residues of the protein (defined as hot-spot residues). Improving the interaction with hot-spot residues of ER alpha offers a promising avenue for obtaining novel SERDs. In this study, pharmacophore modeling, molecular mechanics/generalized Born surface area (MM/GBSA), and amino-acid mutation were combined to determine several hot-spot residues. Focusing on the interaction with these hot-spot residues, hit fragments A1-A3 and A9 were virtually screened from two fragment libraries. Finally, these hit fragments were linked to generate compounds B1-B3, and their biological activities were evaluated. Remarkably, compound B1 exhibited potent antitumor activity against MCF-7 cells (IC50 = 4.21 nM), favorable ER alpha binding affinity (K-i = 14.6 nM), and excellent ER alpha degradative ability (DC50 = 9.7 nM), which indicated its potential to evolve as a promising SERD for breast cancer treatment.

Automated summary

In this study, hot-spot residues of ERα were identified using pharmacophore modeling, molecular mechanics/generalized Born surface area (MM/GBSA), and amino-acid mutation. Hit fragments were virtually screened and linked to generate compounds, among which compound B1 showed potential for breast cancer treatment.