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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
In-silico discovery of novel PARP1 inhibitors for BRCA-mutated TNBC
Shivani Yadav1, Prankur Awasthi1, Ritika Sinha1
1Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow, 226028 India.
Abstract:
Triple-negative breast cancer is an aggressive subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, which renders it insensitive to most conventional therapies. Inhibition of PARP1 has been pointed out as a promising approach for BRCA1/2-mutated cancers due to a synthetic lethality mechanism. This study presents an integrated in-silico drug discovery workflow for the identification of new generation analogues of clinically approved drugs Olaparib and Talazoparib as potential PARP1 inhibitors. Structural analogues were retrieved from the ZINC database, and their affinity was screened by molecular docking. Drug-likeness and ADMET properties of docked analogues were further evaluated. Top candidates were then subjected to MD simulation and MM/GBSA binding free energy calculation to validate interaction stability and pharmacological potential. The combined computational results highlight several leads with a good binding profile, stability, and drug-like properties, thus representing promising therapeutic leads targeting PARP1 in BRCA-mutated TNBC. Overall, this study has underlined the usefulness of integrated in-silico approaches to accelerate the discovery of optimized PARP1 inhibitors for targeted cancer therapy.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s40203-025-00543-x.
Insights
This study identifies novel PARP1 inhibitors for triple-negative breast cancer (TNBC) using computational methods. Promising drug candidates were discovered for BRCA-mutated TNBC, offering new therapeutic avenues.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies due to absent estrogen, progesterone, and HER2 receptors.
- PARP1 inhibition is a promising strategy for BRCA1/2-mutated cancers via synthetic lethality.
Purpose of the Study:
- To identify novel PARP1 inhibitors for BRCA-mutated TNBC.
- To develop new analogues of Olaparib and Talazoparib using an integrated in-silico drug discovery workflow.
Main Methods:
- Retrieved structural analogues from the ZINC database.
- Screened compound affinity using molecular docking.
- Evaluated drug-likeness and ADMET properties.
- Validated interactions with MD simulation and MM/GBSA calculations.
Main Results:
- Identified several lead compounds with favorable binding profiles and stability.
- Top candidates exhibited good drug-like properties.
- Computational results validated the potential of identified analogues as PARP1 inhibitors.
Conclusions:
- Integrated in-silico approaches effectively accelerate the discovery of optimized PARP1 inhibitors.
- Identified compounds represent promising therapeutic leads for BRCA-mutated TNBC.
- This workflow aids in developing targeted cancer therapies.
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