Evaluation of binding and antagonism/downregulation of brilanestrant molecule in estrogen receptor-α via quantum mechanics/molecular mechanics, molecular dynamics and binding free energy calculations.

The resistance to the endocrine therapy of breast cancer leads to the emergence of new class of drugs that downregulates the estrogen receptor action known as selective estrogen receptor downregulators (SERDs). The first approved SERD is fluvestrant; after this, there are several downregulators evolved and are in clinical trials, in which the brilanestrant (BRI) molecule shows nM range of binding affinity and efficacy. In the present study, to understand the binding nature of BRI molecule in the active site of ERα, the molecular docking analysis has been performed. Further, the QM/MM calculations were performed for the BRI-ERα complex to analyze the charge density distribution of intermolecular interactions. The molecular dynamics (MD) simulation was employed to understand the stability and binding mechanism of BRI molecule through root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF) and binding free energy calculations. From the MD simulation trajectory analysis, the alterations of Helix12 conformation and the key residue (Lys529), which is responsible for the ERα downregulation, have been identified. Further, the interaction between the H3 and H12 regions was identified for the antagonism of BRI molecule. The current study led us to understand the binding mechanism, antagonism and downregulation of BRI molecule, and this knowledge is essential to design novel SERDs for the treatment of endocrine-resistant positive breast cancer.Communicated by Ramaswamy H. Sarma.

Investigation of binding mechanism and downregulation of elacestrant for wild and L536S mutant estrogen receptor-α through molecular dynamics simulation and binding free energy analysis.

The selective estrogen receptor downregulators (SERDs) are the new emerging class of drugs that are used for the treatment of endocrine resistance breast cancer. Elacestrant (ELA) is a new SERD, currently it is in phase II clinical trial. To understand the ELA-ERα interactions, the molecular docking analysis has been carried out. The ELA molecule binds with the helices H3, H5, H6, and H11 and forms important intermolecular interactions. In addition to this, the tetrahydronapthalene and phenyl rings of ELA are forming T-shaped π···π interactions with the Phe404 and Trp383 residues. Further to understand the stability and flexibility of ELA molecule in the active site of wild and mutated L536S ERα, 100ns molecular dynamics (MD) simulation was performed for both complexes. Interestingly, the MD analysis of wild complex revealed an interaction between ELA and the Asn532 of H11, which is an essential interaction for the downregulation/degradation of ERα, whereas this interaction is not observed in the mutated complex. The drug binding mechanism and H12 dynamics have been elucidated from the analysis of hydrogen bonding interactions and the secondary structure analysis. To explore the binding affinity of ELA molecule, the binding free energy and normal mode analyses were carried out. The per residue decomposition analysis also performed, which shows the contribution of individual amino acids. The principal component analysis and residue interaction network analysis were used to identify the modifications and the interaction between the residues. From the results of different analysis, the inhibition mechanism and downregulation of ERα-ELA complex has been investigated. © 2019 Wiley Periodicals, Inc.