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Bioinformation. 2019 Apr 30;15(5):321-332. doi: 10.6026/97320630015321. eCollection 2019.

Virtual screening of novel compounds as potential ER-alpha inhibitors.

Author information

1
Centre for Biotechnology, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad, Telungana, India.

Abstract

Majority of breast cancers diagnosed today are estrogen receptor (ER)-positive, however, progesterone receptor-positive (PR-positive) is also responsible for breast cancer. Tumors that are ER/PR-positive are much more likely to respond to hormone therapy than tumors that are ER/PR-negative. Nearly 105 ERa inhibitors from literature when docked resulted in 31 compounds (pyrazolo[1,5-a]pyrimidine analogs and chromen-2-one derivatives) with better binding affinities. The maximum score obtained was -175.282 kcal/mol for compound, [2-(4- Fluoro-phenylamino)-pyridin-3-yl]-{4-[2-phenyl-7- (3, 4, 5-trimethoxy-phenyl)-pyrazolo[1,5-a]pyrimidine-5-carbonyl]-piperazin-1-yl}-methanone. The major H-bond interactions are observed with Thr347. In pursuit to identify novel ERa inhibitory ligands, virtual screening was carried out by docking pyrazole, bipyrazole, thiazole, thiadiazole etc scaffold analogs from literature.34 bipyrazoles from literature revealed Compound 2, ethyl 5-amino-1-(5-amino-3-anilino-4-ethoxycarbonyl-pyrazol-1-yl)-3-anilino-pyrazole-4-carboxylate, with -175.9 kcal/mol binding affinity with the receptor, where a favourable H-bond was formed with Thr347.On the other hand, screening 2035 FDA approved drugs from Drug Bank database resulted in 11 drugs which showed better binding affinities than ERa bound tamoxifen. Consensus scoring using 5 scoring schemes such as Mol Dock score, mcule, SwissDock, Pose&Rank and DSX respectively resulted in better rank-sumsfor Lomitapide, Itraconazole, Cobicistat, Azilsartanmedoxomil, and Zafirlukast.

KEYWORDS:

ERa; bipyrazoles; drug Bank; estrogen; molecular docking; virtual screening

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