Identification of novel 5-lipoxygenase-activating protein (FLAP) inhibitors by an integrated method of pharmacophore virtual screening, docking, QSAR and ADMET analyses

Rullah, Kamal and Roney, Miah and Ibrahim, Zalikha and Shamsudin, Nur Farisya and Islami, Deri and Ahmed, Qamar Uddin and Wai, Lam Kok and Mohd Aluwi, Mohd Fadhlizil Fasihi (2022) 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. pp. 1-21. ISSN 2737-4165 E-ISSN 2737-4173 (In Press)

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Abstract

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 (r2pred=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.

Item Type:	Article (Journal)
Uncontrolled Keywords:	Docking; 2D- and 3D-QSAR; pharmacophore; virtual screening; 5-lipoxygenase-activating protein (FLAP); inflammation.
Subjects:	R Medicine > RS Pharmacy and materia medica > RS403 Materia Medica-Pharmaceutical Chemistry
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Pharmacy > Department of Pharmaceutical Chemistry Kulliyyah of Pharmacy
Depositing User:	Dr Kamal Rullah
Date Deposited:	29 Dec 2022 08:05
Last Modified:	29 Dec 2022 08:05
URI:	http://irep.iium.edu.my/id/eprint/102290

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