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Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating
F A Dain Md Opo1,2, Saleh Alkarim1,2,3, Ghadeer I Alrefaei4
1Department of Biological Science, Faculty of Sciences, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia.
Abstract:
The mortality of cancer patients with neuroblastoma is increasing due to the limited availability of specific treatment options. Few drug candidates for combating neuroblastoma have been developed, and identifying novel therapeutic candidates against the disease is an urgent issue. It has been found that muc-N protein is amplified in one-third of human neuroblastomas and expressed as an attractive drug target against the disease. The myc-N protein interferes with the bromodomain and extraterminal (BET) family proteins. Pharmacologically inhibition of the protein potently depletes MYCN in neuroblastoma cells. BET inhibitors target MYCN transcription and show therapeutic efficacy against neuroblastoma. Therefore, the study aimed to identify potential inhibitors against the BET family protein, specifically Brd4 (brodamine-containing protein 4), to hinder the activity of neuroblastoma cells. To identify effective molecular candidates against the disease, a structure-based pharmacophore model was created for the binding site of the Brd4 protein. The pharmacophore model generated from the protein Brd4 was validated to screen potential natural active compounds. The compounds identified through the pharmacophore-model-based virtual-screening process were further screened through molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, and molecular dynamics (MD) simulation approach. The pharmacophore-model-based screening process initially identified 136 compounds, further evaluated based on molecular docking, ADME analysis, and toxicity approaches, identifying four compounds with good binding affinity and lower side effects. The stability of the selected compounds was also confirmed by dynamic simulation and molecular mechanics with generalized Born and surface area solvation (MM-GBSA) methods. Finally, the study identified four natural lead compounds, ZINC2509501, ZINC2566088, ZINC1615112, and ZINC4104882, that will potentially inhibit the activity of the desired protein and help to fight against neuroblastoma and related diseases. However, further evaluations through in vitro and in vivo assays are suggested to identify their efficacy against the desired protein and disease.
Insights
This study identifies four natural compounds that may inhibit MYCN activity in neuroblastoma cells by targeting Brd4 protein. These compounds show potential as new therapeutic candidates for neuroblastoma treatment.
Area of Science:
- Oncology
- Drug Discovery
- Computational Chemistry
Background:
- Neuroblastoma mortality is rising due to limited treatment options.
- MYCN protein amplification in neuroblastoma presents a therapeutic target.
- Bromodomain and extraterminal (BET) family proteins, including Brd4, are implicated in MYCN regulation.
Purpose of the Study:
- To identify novel therapeutic agents targeting Brd4 for neuroblastoma treatment.
- To develop a structure-based pharmacophore model for Brd4 inhibitors.
- To screen and validate natural compounds as potential Brd4 inhibitors.
Main Methods:
- Generated and validated a structure-based pharmacophore model for Brd4.
- Performed virtual screening of natural compounds against the Brd4 pharmacophore model.
- Utilized molecular docking, ADME/toxicity analysis, and molecular dynamics simulations for compound evaluation.
Main Results:
- Identified four natural compounds (ZINC2509501, ZINC2566088, ZINC1615112, ZINC4104882) with high binding affinity and low predicted toxicity.
- Validated compound stability using molecular dynamics and MM-GBSA methods.
- The identified compounds show potential to inhibit Brd4 activity and MYCN transcription.
Conclusions:
- Four natural compounds were identified as promising lead candidates for neuroblastoma therapy.
- These compounds target the Brd4 protein, a key regulator in neuroblastoma.
- Further in vitro and in vivo studies are recommended to confirm efficacy.
