A New Class of Pure Estrogen Alpha Receptor Antagonists; Design, Synthesis and in-vitro Screening

Author(s): Akbar John Jameera Begam, Katike Ahamed Basheer, Selvaraj Jubie*, Srikanth Jupudi, Mohammed Afzal Azam, Palanisamy Dhanabal.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 1 , 2019

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Graphical Abstract:


Background: In view of the estrogenic receptor inhibitory properties of coumarin nucleus, long chain nature of fatty acid and anti-breast cancer activity of fatty acids, it was proposed to attach long chain fatty acids at 3rd,4th and 7th position of coumarin nucleus and evaluate for their anti-breast cancer activity through suitable in-vitro methods.

Methods: The present study focuses a library of fatty acid coumarin conjugates as ligands to the ligand-binding domain of the human estrogen receptor α (PDB ID 2IOG) and their binding affinities using GLIDE module of Schrodinger after ascertaining their drug-likeness with QIKPROP. The compounds LNAC 8, SAC 1 and OAC 5 are the best hits based on their docking scores as well as the Prime MM-GBSA free energy of binding. Based on the in-silico results and synthetic feasibility the compounds SAC 1 PAC 1 and OAC 1 are synthesized, characterized and investigated for their time interval growth inhibitory effect on MCF-7 which is an ER positive breast cancer cell lines.

Results: SAC 1, showed better in vitro growth inhibitory effect in sub micromolar range as compared to Tamoxifen, a standard estrogen receptor modulator.

Conclusion: Conclusively, in silico molecular docking studies have been very useful in predicting the pharmacokinetic profiles and the binding affinities of new hits before a detailed preclinical and clinical evaluation.

Keywords: Estrogen receptor, coumarin, fatty acids, cytotoxicity, GLIDE, MMGBSA.

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Article Details

Year: 2019
Page: [66 - 81]
Pages: 16
DOI: 10.2174/1570180815666180327124634
Price: $58

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