Pyronaridine as a Bromodomain-Containing Protein 4- N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation

Mahmoud A A Ibrahim; Mahmoud M H Abdelhamid; Khlood A A Abdeljawaad; Alaa H M Abdelrahman; Gamal A H Mekhemer; Peter A Sidhom; Shaban R M Sayed; Paul W Paré; Mohamed-Elamir F Hegazy; Tamer Shoeib

doi:10.3390/molecules28155713

Pyronaridine as a Bromodomain-Containing Protein 4- N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation

Molecules. 2023 Jul 28;28(15):5713. doi: 10.3390/molecules28155713.

Affiliations

¹ Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt.
² School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
⁴ Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
⁵ Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
⁶ Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza 12622, Egypt.
⁷ Department of Chemistry, The American University in Cairo, New Cairo 11835, Egypt.

Abstract

BRD4 (bromodomain-containing protein 4) is an epigenetic reader that realizes histone proteins and promotes the transcription of genes linked to cancer progression and non-cancer diseases such as acute heart failure and severe inflammation. The highly conserved N-terminal bromodomain (BD1) recognizes acylated lysine residues to organize the expression of genes. As such, BD1 is essential for disrupting BRD4 interactions and is a promising target for cancer treatment. To identify new BD1 inhibitors, a SuperDRUG2 database that contains more than 4600 pharmaceutical compounds was screened using in silico techniques. The efficiency of the AutoDock Vina1.1.2 software to anticipate inhibitor-BRD4-BD1 binding poses was first evaluated based on the co-crystallized R6S ligand in complex with BRD4-BD1. From database screening, the most promising BRD4-BD1 inhibitors were subsequently submitted to molecular dynamics (MD) simulations integrated with an MM-GBSA approach. MM-GBSA computations indicated promising BD1 binding with a benzonaphthyridine derivative, pyronaridine (SD003509), with an energy prediction (ΔG_binding) of -42.7 kcal/mol in comparison with -41.5 kcal/mol for a positive control inhibitor (R6S). Pharmacokinetic properties predicted oral bioavailability for both ligands, while post-dynamic analyses of the BRD4-BD1 binding pocket demonstrated greater stability for pyronaridine. These results confirm that in silico studies can provide insight into novel protein-ligand regulators, specifically that pyronaridine is a potential cancer drug candidate.

Keywords: SuperDRUG2 database; bromodomain-containing protein 4; cancer disease; molecular docking; molecular dynamics simulations.

MeSH terms

Bromodomain Containing Proteins
Cell Cycle Proteins / metabolism
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation*
Nuclear Proteins* / metabolism
Transcription Factors / metabolism

Substances

Nuclear Proteins
pyronaridine
Bromodomain Containing Proteins
Transcription Factors
Ligands
Cell Cycle Proteins

Grants and funding

This research received no external funding.