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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...

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Main Authors: Rullah, Kamal, Roney, Miah, Zalikha, Ibrahim, Nur Farisya, Shamsudin, Deri, Islami, Qamar Uddin, Ahmed, Kok, Wai Lam, Mohd Fadhlizil Fasihi, Mohd Aluwi
Format: Article
Language:English
Published: World Scientific Publishing 2023
Subjects:
Q Science (General)
QD Chemistry
TP Chemical technology
Online Access:http://umpir.ump.edu.my/id/eprint/40039/1/Identification%20of%20novel%205-lipoxygenase-activating%20protein_abst.pdf
http://umpir.ump.edu.my/id/eprint/40039/
https://doi.org/10.1142/S2737416523500059
https://doi.org/10.1142/S2737416523500059
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spelling my.ump.umpir.400392024-01-16T07:15:00Z 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
institution Universiti Malaysia Pahang Al-Sultan Abdullah
building UMPSA Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaysia Pahang Al-Sultan Abdullah
content_source UMPSA Institutional Repository
url_provider http://umpir.ump.edu.my/
language English
topic Q Science (General)
QD Chemistry
TP Chemical technology
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
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.
format Article
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
title 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_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_sort identification of novel 5-lipoxygenase-activating protein (flap) inhibitors by an integrated method of pharmacophore virtual screening, docking, qsar and admet analyses
publisher World Scientific Publishing
publishDate 2023
url http://umpir.ump.edu.my/id/eprint/40039/1/Identification%20of%20novel%205-lipoxygenase-activating%20protein_abst.pdf
http://umpir.ump.edu.my/id/eprint/40039/
https://doi.org/10.1142/S2737416523500059
https://doi.org/10.1142/S2737416523500059
_version_ 1822924085679620096
score 13.235362

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