Drug repurposing for the identification of new Bcl-2 inhibitors: In vitro, STD-NMR, molecular docking, and dynamic simulation studies.
Humans
Molecular Docking Simulation
Proto-Oncogene Proteins c-bcl-2
/ metabolism
Drug Repositioning
Carvedilol
Clomipramine
Paroxetine
Antineoplastic Agents
/ chemistry
Molecular Dynamics Simulation
Magnetic Resonance Spectroscopy
Clomiphene
Citrates
Drug Screening Assays, Antitumor
Cell Line, Tumor
Bcl-2 protein
Carvedilol
Clomifene
Clomipramine
Drug repurposing
Paroxetine
STD-NMR
Journal
Life sciences
ISSN: 1879-0631
Titre abrégé: Life Sci
Pays: Netherlands
ID NLM: 0375521
Informations de publication
Date de publication:
01 Dec 2023
01 Dec 2023
Historique:
received:
08
08
2023
revised:
06
10
2023
accepted:
14
10
2023
medline:
20
11
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
ppublish
Résumé
The anti-apoptotic protein B-Cell Lymphoma 2 (Bcl-2) is a key target for the development of anti-cancer agents, as its overexpression can render cancer cells resistant to chemotherapeutic treatments. The current study has systematically evaluated a library of FDA-approved drugs for Bcl-2 inhibition using a drug repurposing strategy via in vitro, biophysical, and in-silico techniques. In vitro anticancer activity was performed, followed by apoptosis assay. The selected compounds were subjected to Saturation Transfer Difference Nuclear Magnetic Resonance (STD-NMR) spectroscopy, molecular docking, and molecular dynamic simulation for ligand-protein interactions. In the initial screening, seventy-five (75) drugs were evaluated against the HL-60 (human blood promyelocytic leukemia) cancer cell line. Among them, paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate showed significant anti-proliferative activity (IC This study, identifies paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate as significant Bcl-2 inhibitors and needs further pre-clinical and clinical studies for potential anti-cancer agents' evaluation.
Sections du résumé
BACKGROUND
BACKGROUND
The anti-apoptotic protein B-Cell Lymphoma 2 (Bcl-2) is a key target for the development of anti-cancer agents, as its overexpression can render cancer cells resistant to chemotherapeutic treatments.
AIMS AND OBJECTIVES
OBJECTIVE
The current study has systematically evaluated a library of FDA-approved drugs for Bcl-2 inhibition using a drug repurposing strategy via in vitro, biophysical, and in-silico techniques.
MATERIALS AND METHODS
METHODS
In vitro anticancer activity was performed, followed by apoptosis assay. The selected compounds were subjected to Saturation Transfer Difference Nuclear Magnetic Resonance (STD-NMR) spectroscopy, molecular docking, and molecular dynamic simulation for ligand-protein interactions.
KEY FINDINGS
RESULTS
In the initial screening, seventy-five (75) drugs were evaluated against the HL-60 (human blood promyelocytic leukemia) cancer cell line. Among them, paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate showed significant anti-proliferative activity (IC
SIGNIFICANCE
CONCLUSIONS
This study, identifies paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate as significant Bcl-2 inhibitors and needs further pre-clinical and clinical studies for potential anti-cancer agents' evaluation.
Identifiants
pubmed: 37858717
pii: S0024-3205(23)00816-0
doi: 10.1016/j.lfs.2023.122181
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins c-bcl-2
0
Carvedilol
0K47UL67F2
Clomipramine
NUV44L116D
Paroxetine
41VRH5220H
Antineoplastic Agents
0
Clomiphene
1HRS458QU2
Citrates
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
122181Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.