Structure-based virtual screening for identification of potential CDC20 inhibitors and their therapeutic evaluation in breast cancer
Abstract Cell division cycle 20 (CDC20), a critical partner of anaphase promoting complex (APC/C), is indispensably required for metaphase-to-anaphase transition. CDC20 overexpression in TNBC breast cancer patients has been found to be correlated with poor prognosis, hence, we aimed to target CDC20 for TNBC therapeutics. In silico molecular docking of large-scale chemical libraries (phytochemicals/synthetic drugs) against CDC20 protein structure identified five synthetic drugs and four phytochemicals as potential hits interacting with CDC20 active site. The molecular selection was done based on docking scores, binding interactions, binding energies and MM/GBSA scores. Further, we analysed ADME profiles for all the hits and identified lidocaine, an aminoamide anaesthetic group of synthetic drug, with high drug-likeness properties. We explored the anti-tumorigenic effects of lidocaine on MDA-MB-231 TNBC breast cancer cells, which resulted in increased growth inhibition in dose-dependent manner. The molecular mechanism behind the cell viability defect mediated by lidocaine was found to be induction of G2/M cell cycle arrest and cellular apoptosis. Notably, lidocaine treatment of TNBC cells also resulted in downregulation of CDC20 gene expression. Thus, this study identifies lidocaine as a potential anti-neoplastic agent for TNBC cells emphasizing CDC20 as a suitable therapeutic target for breast cancer..
| Medienart: |
Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
3 Biotech - 13(2023), 5 vom: 26. Apr. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Das, Amiya [VerfasserIn] |
|---|
| Links: |
Volltext [lizenzpflichtig] |
|---|
| Themen: |
|---|
| Anmerkungen: |
© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
|---|
| doi: |
10.1007/s13205-023-03554-7 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
OLC2134718072 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | OLC2134718072 | ||
| 003 | DE-627 | ||
| 005 | 20230510163241.0 | ||
| 007 | tu | ||
| 008 | 230510s2023 xx ||||| 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s13205-023-03554-7 |2 doi | |
| 035 | |a (DE-627)OLC2134718072 | ||
| 035 | |a (DE-He213)s13205-023-03554-7-p | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Das, Amiya |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Structure-based virtual screening for identification of potential CDC20 inhibitors and their therapeutic evaluation in breast cancer |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a © King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. | ||
| 520 | |a Abstract Cell division cycle 20 (CDC20), a critical partner of anaphase promoting complex (APC/C), is indispensably required for metaphase-to-anaphase transition. CDC20 overexpression in TNBC breast cancer patients has been found to be correlated with poor prognosis, hence, we aimed to target CDC20 for TNBC therapeutics. In silico molecular docking of large-scale chemical libraries (phytochemicals/synthetic drugs) against CDC20 protein structure identified five synthetic drugs and four phytochemicals as potential hits interacting with CDC20 active site. The molecular selection was done based on docking scores, binding interactions, binding energies and MM/GBSA scores. Further, we analysed ADME profiles for all the hits and identified lidocaine, an aminoamide anaesthetic group of synthetic drug, with high drug-likeness properties. We explored the anti-tumorigenic effects of lidocaine on MDA-MB-231 TNBC breast cancer cells, which resulted in increased growth inhibition in dose-dependent manner. The molecular mechanism behind the cell viability defect mediated by lidocaine was found to be induction of G2/M cell cycle arrest and cellular apoptosis. Notably, lidocaine treatment of TNBC cells also resulted in downregulation of CDC20 gene expression. Thus, this study identifies lidocaine as a potential anti-neoplastic agent for TNBC cells emphasizing CDC20 as a suitable therapeutic target for breast cancer. | ||
| 650 | 4 | |a ADME | |
| 650 | 4 | |a Antitumor agents | |
| 650 | 4 | |a GLIDE | |
| 650 | 4 | |a MM/GBSA | |
| 650 | 4 | |a TNBC | |
| 700 | 1 | |a Sharma, Hitesh Kumar |4 aut | |
| 700 | 1 | |a Lather, Viney |4 aut | |
| 700 | 1 | |a Pandita, Deepti |0 (orcid)0000-0002-3644-7045 |4 aut | |
| 700 | 1 | |a Agarwal, Pallavi |0 (orcid)0000-0003-3139-5589 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t 3 Biotech |d Springer International Publishing, 2013 |g 13(2023), 5 vom: 26. Apr. |w (DE-627)1667343041 |w (DE-600)2974829-X |x 2190-572X |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2023 |g number:5 |g day:26 |g month:04 |
| 856 | 4 | 1 | |u https://doi.org/10.1007/s13205-023-03554-7 |z lizenzpflichtig |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a SYSFLAG_A | ||
| 912 | |a GBV_OLC | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2023 |e 5 |b 26 |c 04 | ||