Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma
<div><p>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 issu...
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2022
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| _version_ | 1864513518652358656 |
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| author | F A Dain Md Opo (14123109) |
| author2 | Saleh Alkarim (5914538) Ghadeer I. Alrefaei (18421455) Mohammad Habibur Rahman Molla (13902168) Nouf H. Alsubhi (18421458) Faisal Alzahrani (16940155) Foysal Ahammad (9286524) |
| author2_role | author author author author author author |
| author_facet | F A Dain Md Opo (14123109) Saleh Alkarim (5914538) Ghadeer I. Alrefaei (18421455) Mohammad Habibur Rahman Molla (13902168) Nouf H. Alsubhi (18421458) Faisal Alzahrani (16940155) Foysal Ahammad (9286524) |
| author_role | author |
| dc.creator.none.fl_str_mv | F A Dain Md Opo (14123109) Saleh Alkarim (5914538) Ghadeer I. Alrefaei (18421455) Mohammad Habibur Rahman Molla (13902168) Nouf H. Alsubhi (18421458) Faisal Alzahrani (16940155) Foysal Ahammad (9286524) |
| dc.date.none.fl_str_mv | 2022-10-13T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/cimb44100329 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Pharmacophore-Model-Based_Virtual-Screening_Approaches_Identified_Novel_Natural_Molecular_Candidates_for_Treating_Human_Neuroblastoma/25663836 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Microbiology neuroblastoma MYCN Brd4 molecular docking pharmacophore model side effects dynamic simulation |
| dc.title.none.fl_str_mv | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><p>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.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Current Issues in Molecular Biology<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/cimb44100329" target="_blank">https://dx.doi.org/10.3390/cimb44100329</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_f49c438e4d9c1f88f1236615224d88f3 |
| identifier_str_mv | 10.3390/cimb44100329 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25663836 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human NeuroblastomaF A Dain Md Opo (14123109)Saleh Alkarim (5914538)Ghadeer I. Alrefaei (18421455)Mohammad Habibur Rahman Molla (13902168)Nouf H. Alsubhi (18421458)Faisal Alzahrani (16940155)Foysal Ahammad (9286524)Biological sciencesMicrobiologyneuroblastomaMYCNBrd4molecular dockingpharmacophore modelside effectsdynamic simulation<div><p>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.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Current Issues in Molecular Biology<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/cimb44100329" target="_blank">https://dx.doi.org/10.3390/cimb44100329</a></p>2022-10-13T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/cimb44100329https://figshare.com/articles/journal_contribution/Pharmacophore-Model-Based_Virtual-Screening_Approaches_Identified_Novel_Natural_Molecular_Candidates_for_Treating_Human_Neuroblastoma/25663836CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/256638362022-10-13T03:00:00Z |
| spellingShingle | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma F A Dain Md Opo (14123109) Biological sciences Microbiology neuroblastoma MYCN Brd4 molecular docking pharmacophore model side effects dynamic simulation |
| status_str | publishedVersion |
| title | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma |
| title_full | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma |
| title_fullStr | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma |
| title_full_unstemmed | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma |
| title_short | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma |
| title_sort | Pharmacophore-Model-Based Virtual-Screening Approaches Identified Novel Natural Molecular Candidates for Treating Human Neuroblastoma |
| topic | Biological sciences Microbiology neuroblastoma MYCN Brd4 molecular docking pharmacophore model side effects dynamic simulation |