Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses
This study explored a series of reported 5-lipoxygenase-activating protein (FLAP) inhibitors to understand their structural requirements and identify potential new inhibitor scaffolds through automated unbiased procedures. Docking studies have revealed that inhibitor binding affinity can be influenc...
| Những tác giả chính: | , , , , , , , |
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| Định dạng: | Bài viết |
| Ngôn ngữ: | English |
| Được phát hành: |
World Scientific Publishing
2023
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| Những chủ đề: | |
| Truy cập trực tuyến: | http://umpir.ump.edu.my/id/eprint/40039/1/Identification%20of%20novel%205-lipoxygenase-activating%20protein_abst.pdf |
| _version_ | 1825815409232707584 |
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| author | Rullah, Kamal Roney, Miah Zalikha, Ibrahim Nur Farisya, Shamsudin Deri, Islami Qamar Uddin, Ahmed Kok, Wai Lam Mohd Fadhlizil Fasihi, Mohd Aluwi |
| author_facet | Rullah, Kamal Roney, Miah Zalikha, Ibrahim Nur Farisya, Shamsudin Deri, Islami Qamar Uddin, Ahmed Kok, Wai Lam Mohd Fadhlizil Fasihi, Mohd Aluwi |
| author_sort | Rullah, Kamal |
| collection | UMP |
| description | This study explored a series of reported 5-lipoxygenase-activating protein (FLAP) inhibitors to understand their structural requirements and identify potential new inhibitor scaffolds through automated unbiased procedures. Docking studies have revealed that inhibitor binding affinity can be influenced by several key binding interactions with Phe114 and Lys116 from chain B and Val21, Phe25, His28 and Lys29 from chain C in the FLAP-binding site. A ligand-based alignment three-dimensional (3D)-quantitative structure-activity relationship (QSAR) was adopted, resulting in a robust model with a statistically significant noncross validated coefficient (r2=0.992), a cross-validated correlation coefficient (q2=0.681) and a predictive squared correlation coefficient (rpred2=0.736). Overall, the analysis revealed the important electrostatic and steric attributes responsible for the FLAP inhibitory activity, which appeared to correlate well with the docking results. In addition, two statistically significant two-dimensional (2D)-QSAR models (r2=0.9369, q2=0.889 and r2=0.9679, q2=0.655) were developed by a genetic function approximation (GFA). HypoGen 1, a proposed pharmacophore model, was used for database mining to identify potential new FLAP inhibitors. The bioactivity of the retrieved hits was then evaluated in silico based on the validated QSAR models, followed by pharmacokinetics and toxicity predictions. |
| first_indexed | 2024-03-06T13:13:03Z |
| format | Article |
| id | UMPir40039 |
| institution | Universiti Malaysia Pahang |
| language | English |
| last_indexed | 2024-03-06T13:13:03Z |
| publishDate | 2023 |
| publisher | World Scientific Publishing |
| record_format | dspace |
| spelling | UMPir400392024-01-16T07:15:00Z http://umpir.ump.edu.my/id/eprint/40039/ Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses Rullah, Kamal Roney, Miah Zalikha, Ibrahim Nur Farisya, Shamsudin Deri, Islami Qamar Uddin, Ahmed Kok, Wai Lam Mohd Fadhlizil Fasihi, Mohd Aluwi Q Science (General) QD Chemistry TP Chemical technology This study explored a series of reported 5-lipoxygenase-activating protein (FLAP) inhibitors to understand their structural requirements and identify potential new inhibitor scaffolds through automated unbiased procedures. Docking studies have revealed that inhibitor binding affinity can be influenced by several key binding interactions with Phe114 and Lys116 from chain B and Val21, Phe25, His28 and Lys29 from chain C in the FLAP-binding site. A ligand-based alignment three-dimensional (3D)-quantitative structure-activity relationship (QSAR) was adopted, resulting in a robust model with a statistically significant noncross validated coefficient (r2=0.992), a cross-validated correlation coefficient (q2=0.681) and a predictive squared correlation coefficient (rpred2=0.736). Overall, the analysis revealed the important electrostatic and steric attributes responsible for the FLAP inhibitory activity, which appeared to correlate well with the docking results. In addition, two statistically significant two-dimensional (2D)-QSAR models (r2=0.9369, q2=0.889 and r2=0.9679, q2=0.655) were developed by a genetic function approximation (GFA). HypoGen 1, a proposed pharmacophore model, was used for database mining to identify potential new FLAP inhibitors. The bioactivity of the retrieved hits was then evaluated in silico based on the validated QSAR models, followed by pharmacokinetics and toxicity predictions. World Scientific Publishing 2023-02 Article PeerReviewed pdf en http://umpir.ump.edu.my/id/eprint/40039/1/Identification%20of%20novel%205-lipoxygenase-activating%20protein_abst.pdf Rullah, Kamal and Roney, Miah and Zalikha, Ibrahim and Nur Farisya, Shamsudin and Deri, Islami and Qamar Uddin, Ahmed and Kok, Wai Lam and Mohd Fadhlizil Fasihi, Mohd Aluwi (2023) Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses. Journal of Computational Biophysics and Chemistry, 22 (1). 77 -97. ISSN 2737-4173. (Published) https://doi.org/10.1142/S2737416523500059 https://doi.org/10.1142/S2737416523500059 |
| spellingShingle | Q Science (General) QD Chemistry TP Chemical technology Rullah, Kamal Roney, Miah Zalikha, Ibrahim Nur Farisya, Shamsudin Deri, Islami Qamar Uddin, Ahmed Kok, Wai Lam Mohd Fadhlizil Fasihi, Mohd Aluwi Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses |
| title | Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses |
| title_full | Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses |
| title_fullStr | Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses |
| title_full_unstemmed | Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses |
| title_short | Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses |
| title_sort | identification of novel 5 lipoxygenase activating protein flap inhibitors by an integrated method of pharmacophore virtual screening docking qsar and admet analyses |
| topic | Q Science (General) QD Chemistry TP Chemical technology |
| url | http://umpir.ump.edu.my/id/eprint/40039/1/Identification%20of%20novel%205-lipoxygenase-activating%20protein_abst.pdf |
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