Investigation of binding mechanism and downregulation of elacestrant for wild and L536S mutant estrogen receptor-alpha through molecular dynamics simulation and binding free energy analysis.
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Chinnasamy K, Saravanan M, Poomani K
Investigation of binding mechanism and downregulation of elacestrant for wild and L536S mutant estrogen receptor-alpha through molecular dynamics simulation and binding free energy analysis.
J Comput Chem. 2020 Jan 15;41(2):97-109. doi: 10.1002/jcc.26076. Epub 2019 Oct 10.
- PubMed ID
- 31602686 [ View in PubMed]
- Abstract
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-ERalpha 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 pi...pi 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 ERalpha, 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 ERalpha, 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 ERalpha-ELA complex has been investigated. (c) 2019 Wiley Periodicals, Inc.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Elacestrant Estrogen receptor alpha Protein Humans UnknownAntagonistDetails