Identification of biological targets through the correlation between cell line chemosensitivity and protein expression pattern

Lauria, Antonino; Monica, Gabriele La; Gentile, Carla; Mannino, Giuseppe; Martorana, Annamaria; Peri, Daniele

doi:10.1016/j.drudis.2021.05.013

Cited by 1 publication

(2 citation statements)

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“…To further investigate the putative dual-target mechanism of action of the selected compounds, an additional correlation analysis between drug activity and protein expression data, which we recently proposed and applied [ 76 , 77 ], was conducted.…”

Section: Resultsmentioning

confidence: 99%

“…Two large databases of CDK-1 and PARP-1 known modulators were downloaded from the BindingDB [80], a reliable web-accessible source of experimentally determined protein-ligand binding affinities, where the Ki, Kd, IC50, EC50 values, and the corresponding In detail, in the first phase of the protocol, the well-established molecular descriptorbased Biotarget Predictor Tool (BPT), developed by us and available online in the DRUDIT web-platform (DRUg DIscovery Tools, open access web service, www.drudit.com, accessed on 19 July 2023) [75], was applied. Subsequently, structure-based studies of molecular docking were integrated with a new in-house correlation approach to gain more insight into the binding mode and the mechanism of action of the selected hits [76,77]; as a last step, Molecular Dynamic Simulations (MDS) were conducted for the best ranked dual inhibitor on both target protein 3D structures.…”

Section: Ligand-based Template Buildingmentioning

confidence: 99%

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

Bono,

La Monica,

Alamia

et al. 2023

IJMS

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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.

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Section: Resultsmentioning

confidence: 99%