Hormone therapy resistant breast and prostate tumors found to resume growth in hormone independent manner and present a major challenge in drug designing. In order to address the issue, we identify alternate protein targets by elucidating protein-protein and protein-DNA interfaces of ERα and AR and use them to develop new generation of anti-cancer agents. Using the crystal structures of ERα and AR Ligand binding and DNA binding domains, molecular modeling, molecular dynamics simulations, and bioinformatics we identified the hydrogen-bonding contact motifs that are responsible for dimerization and/or DNA recognition. The crucial amino acids of a motif are then grafted on stable helices (alanine and glutamine) in order to develop peptidic inhibitors. In ERα, using the dimerization sequence motif LQXXHQXXAQ (497-506) as a template we have developed designer peptides AAHQALAQAAAAAAAAA and AADQADAQAAAAAAAAA which exhibit significant suppression of ER-expression in MCF-7 breast cancer cell lines. The designer peptides inhibit ERα dimerization – an essential process in ER mediated transcription. In AR, protein-protein binding contacts are insignificant to find a suitable target. The LCAXRXD motif (578-584) of AR that binds with AR and DNA is being studied for its suitability to develop designer peptide.

Drug designing for hormone therapy resistant breast and prostate cancers

255th National Meeting (2018)

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