AUTHOR=Khan Abbas , Ashfaq-Ur-Rehman  , Junaid Muhammad , Li Cheng-Dong , Saleem Shoaib , Humayun Fahad , Shamas Shazia , Ali Syed Shujait , Babar Zainib , Wei Dong-Qing 

TITLE=Dynamics Insights Into the Gain of Flexibility by Helix-12 in ESR1 as a Mechanism of Resistance to Drugs in Breast Cancer Cell Lines

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 6 - 2019

YEAR=2020

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2019.00159

DOI=10.3389/fmolb.2019.00159

ISSN=2296-889X

ABSTRACT=The incedences of breast cancer (BC) is augmented diurnally in women and proved to be the  colossal cause of their death in developed & developing countries. Among total BC cases diagnosed after menopause, 70% of cases are Estrogen Receptor (ER) positive (ER-positive or ER+). Mutations in the LBD (ligand-binding domain) domain of ER has recently been reported to be the major cause of resistance to potent antagonists. In this study, the experimentally reported mutations K303R, E380Q, V392I, S463P, V524E, P535H, P536H, Y537C, Y537N, Y537S, and D538G were analyzed, and the most significant mutations were shortlisted based on multiple analyses. Initial analysis such as mCSM stability, occluded depth analysis, mCSM binding affinity, and FoldX energy changes shortlisted only six mutations to be highly resistant. Finally, simulations of force field-based molecular dynamics (MD on wild type (WT) ERα) on six mERα variants (E380Q, S463P, Y537S, Y537C, Y537N, and D538G) were carried out, to justify mechanism of the resistance. It was observed that these mutations increased the flexibility of the H12. Bonding analysis suggested that previously reported important residue His524 lost bonding upon mutations. Other parameters such as PCA (principal component analysis), DCCM (dynamics cross-correlation), and FEL (free energy landscape) verified that the shortlisted mutations affect the H12 helix, which opens up the co-activator binding conformation. These results provide a deep insight into the mechanism of relative resistance posed to fulvestrant due to mutations in breast cancer. This study will facilitate to understand the important aspects of designing specific and more effective drugs.