Identification of indole-based natural compounds as inhibitors of PARP-1 against triple-negative breast cancer: a computational study

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive kind of breast cancer known to mankind. It is a heterogeneous disease that is formed due to the missing estrogen, progesterone and human epidermal growth factor 2 receptors. Poly(ADP-ribose) polymerase-1 (PARP-1) protein helps in the development of TNBC by repairing the cancer cells, which proliferate and spread metastatically. To determine the potential PARP-1 inhibitors (PARPi), 0.2 million natural products from Universal Natural Product Database were screened using molecular docking and six hit compounds were selected based on their binding affinity towards PARP-1. The bio-availability and drug-like properties of these natural products were evaluated using ADMET analysis. Molecular dynamics simulations were conducted for these complexes for 200 ns to examine their structural stability and dynamic behaviour and further compared with the complex of talazoparib (TALA), an FDA-approved PARPi. Using MM/PBSA calculations, we conclude that the complexes HIT-3 and HIT-5 (−25.64 and −23.14 kcal/mol, respectively) show stronger binding energies with PARP-1 than TALA with PARP-1 (−10.74 kcal/mol). Strong interactions were observed between the compounds and hotspot residues, Asp770, Ala880, Tyr889, Tyr896, Ala898, Asp899 and Tyr907, of PARP-1 due to the existence of various types of non-covalent interactions between the compounds and PARP-1. This research offers critical information about PARPi, which could potentially be incorporated into the treatment of TNBC. Moreover, these findings were validated by comparing them with an FDA-approved PARPi.

Keywords:

• Triple-negative breast cancer
• poly(ADP-ribose) polymerase
• protein-ligand complexes
• molecular dynamics simulations
• binding free energy

Acknowledgments

The authors S.P, K.P and S.M.E.R thank SRM Institute of Science and Technology (SRM-IST) Research Fellowship for her/his research work. The authors also thank SRM-IST for providing the supercomputing facility and financial support. M.P. thanks the Ministry of Electronics and Information Technology (MeitY) Quantum Computing Applications Lab (QCAL) project. The author V.R. thanks the Department of Science and Technology (DST)-INSPIRE Faculty Award [DST/INSPIRE/04/2016/000131 (IFA-16-CH-233)], New Delhi, India for the financial support. We also thank the OpenEye Inc., for providing the academic license to use the docking tools.

Disclosure statement

There are no conflicts of interest to declare.