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Title

Virtual screening of novel compounds as potential ERα inhibitors

 

Authors

J. TilakVijay*, K. Vivek Babu, A. Uma

 

Affiliation

Centre for Biotechnology, Institute of Science &Technology, Jawaharlal Nehru Technological University, Hyderabad, Telungana, India

 

Email

J. TilakVijay E-mail: vijaytilak28@gmail.com

 

Article Type

Research Article

 

Date

Received April 2, 2019; Accepted April 12, 2019; Published April 30, 2019

 

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 ERα 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 ERα 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 ERα 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

molecular docking, virtual screening, ERα, estrogen, bipyrazoles, drug Bank

 

Citation

Tilak Vijay et al. Bioinformation 15(5): 321-332 (2019)

 

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.