Computer-Aided Ligand Discovery for Estrogen Receptor Alpha
Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes ca...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/12/4193 |
| _version_ | 1797565536250363904 |
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| author | Divya Bafna Fuqiang Ban Paul S. Rennie Kriti Singh Artem Cherkasov |
| author_facet | Divya Bafna Fuqiang Ban Paul S. Rennie Kriti Singh Artem Cherkasov |
| author_sort | Divya Bafna |
| collection | DOAJ |
| description | Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery. |
| first_indexed | 2024-03-10T19:13:36Z |
| format | Article |
| id | doaj.art-f9f09f63ae6c4c74923050ec2ad30195 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:13:36Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f9f09f63ae6c4c74923050ec2ad301952023-11-20T03:36:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-06-012112419310.3390/ijms21124193Computer-Aided Ligand Discovery for Estrogen Receptor AlphaDivya Bafna0Fuqiang Ban1Paul S. Rennie2Kriti Singh3Artem Cherkasov4Vancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaVancouver Prostate Centre, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaBreast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.https://www.mdpi.com/1422-0067/21/12/4193estrogen receptorbreast cancercomputer-aided drug designvirtual screening |
| spellingShingle | Divya Bafna Fuqiang Ban Paul S. Rennie Kriti Singh Artem Cherkasov Computer-Aided Ligand Discovery for Estrogen Receptor Alpha International Journal of Molecular Sciences estrogen receptor breast cancer computer-aided drug design virtual screening |
| title | Computer-Aided Ligand Discovery for Estrogen Receptor Alpha |
| title_full | Computer-Aided Ligand Discovery for Estrogen Receptor Alpha |
| title_fullStr | Computer-Aided Ligand Discovery for Estrogen Receptor Alpha |
| title_full_unstemmed | Computer-Aided Ligand Discovery for Estrogen Receptor Alpha |
| title_short | Computer-Aided Ligand Discovery for Estrogen Receptor Alpha |
| title_sort | computer aided ligand discovery for estrogen receptor alpha |
| topic | estrogen receptor breast cancer computer-aided drug design virtual screening |
| url | https://www.mdpi.com/1422-0067/21/12/4193 |
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