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In Silico Mixed Ligand/Structure-Based Design of New CDK-1/PARP-1 Dual Inhibitors as Anti-Breast Cancer Agents.

Authors :
Bono A
La Monica G
Alamia F
Mingoia F
Gentile C
Peri D
Lauria A
Martorana A
Source :
International journal of molecular sciences [Int J Mol Sci] 2023 Sep 06; Vol. 24 (18). Date of Electronic Publication: 2023 Sep 06.
Publication Year :
2023

Abstract

CDK-1 and PARP-1 play crucial roles in breast cancer progression. Compounds acting as CDK-1 and/or PARP-1 inhibitors can induct cell death in breast cancer with a selective synthetic lethality mechanism. A mixed treatment by means of CDK-1 and PARP-1 inhibitors resulted in radical breast cancer cell growth reduction. Inhibitors with a dual target mechanism of action could arrest cancer progression by simultaneously blocking the DNA repair mechanism and cell cycle, resulting in advantageous monotherapy. To this aim, in the present work, we identified compound 645656 with a significant affinity for both CDK-1 and PARP-1 by a mixed ligand- and structure-based virtual screening protocol. The Biotarget Predictor Tool was used at first in a Multitarget mode to filter the large National Cancer Institute (NCI) database. Then, hierarchical docking studies were performed to further screen the compounds and evaluate the ligands binding mode, whose putative dual-target mechanism of action was investigated through the correlation between the antiproliferative activity data and the target proteins' (CDK-1 and PARP-1) expression pattern. Finally, a Molecular Dynamics Simulation confirmed the high stability of the most effective selected compound 645656 in complex with both PARP-1 and CDK-1.

Details

Language :
English
ISSN :
1422-0067
Volume :
24
Issue :
18
Database :
MEDLINE
Journal :
International journal of molecular sciences
Publication Type :
Academic Journal
Accession number :
37762072
Full Text :
https://doi.org/10.3390/ijms241813769