| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Molecules, Vol 28, Iss 15, p 5713 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1420-3049 |
| DOI: |
10.3390/molecules28155713 |
| Popis: |
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 (ΔGbinding) 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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