Modulation of the interaction of BRCA1-RAD51 and BRCA1-AURKA protein complexes by natural metabolites as a possible therapeutic intervention in the cardiotoxic effects of cancer drugs: an in silico approach

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J Biomol Structure Dyn. 2021 Oct. 11: 1-17. doi: 10.1080 / 07391102.2021.1976278. Online before printing.

ABSTRACT

Breast cancer type 1 susceptibility protein (BRCA1) plays an important role in maintaining genome stability and is known to interact with several proteins involved in cellular signaling pathways, gene transcription regulation, and the response to DNA damage. More than 40% of inherited breast cancer cases are due to a BRCA1 mutation. It is also a prognostic marker in patients with non-small cell lung cancer as well as a gatekeeper of cardiac function. It is known that the interaction of mutated BRCA1 with other proteins disrupts the tumor suppression mechanism. Two proteins that interact directly with BRCA1, namely the DNA repair protein RAD51 (RAD51) and Aurora Kinase A (AURKA), which are known to regulate homologous recombination (HR) and the transition of the G / M cell cycle, respectively , form a protein complex with both wild and mutated BRCA1. To analyze the interactions, protein-protein complexes were generated for each protein pair. To combat the cardiotoxic effects of cancer drugs, pharmacokinetically screened natural metabolites from plant, marine, and bacterial sources, and along with FDA-approved cancer drugs as controls, were molecularly docked. Piperolein B and dihydrocircumin were the best-docked natural metabolites in both the RAD51 and AURKA complexes. The analysis of the molecular dynamics simulation (MDS) and calculations of the binding free energy for the best docked natural metabolite and active ingredient for both mutated BRCA1 complexes indicated a better stability of the natural metabolites piperolein B and dihydrocurcumin compared to the active ingredient. Thus, both natural metabolites could be further investigated by wet laboratory experiments for their role against the cardiotoxic effects of cancer drugs. Submitted by Ramaswamy H. Sarma.

PMID:34632941 | DOI:10.1080 / 07391102.2021.1976278

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