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Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches.

ABSTRACT: Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side effects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson's correlation for the construction of quantitative structure-activity relationship (QSAR) models to predict the biological activities of the compounds obtained with virtual screening. The pharmacokinetic/toxicological profiles of the compounds were determined, as well as the binding modes through molecular docking compared to commercial compounds (rofecoxib and celecoxib). The QSAR analysis showed a fit with R = 0.9617, R2 = 0.9250, standard error of estimate (SEE) = 0.2238, and F = 46.2739, with the tetra-parametric regression model. After the analysis, only three promising inhibitors were selected, Z-964, Z-627, and Z-814, with their predicted pIC50 (-log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski's rule of five, which predicts a good oral availability and can be used in in vitro and in vivo tests in the zebrafish model in order to confirm the obtained in silico data.

SUBMITTER: Araujo PHF

PROVIDER: S-EPMC7570943 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches.

Araújo Pedro H F PHF Ramos Ryan S RS da Cruz Jorddy N JN Silva Sebastião G SG Ferreira Elenilze F B EFB de Lima Lúcio R LR Macêdo Williams J C WJC Espejo-Román José M JM Campos Joaquín M JM Santos Cleydson B R CBR

Molecules (Basel, Switzerland) 20200912 18

Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side effects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson's correlation for the construction of quanti ...[more]

PMID: 32932669

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Project description:With the immensely growing outbreaks of hantavirus with still no effective treatment available, there is an urgent need of exploring new computational approaches which will target potential virulent proteins that will eventually reduce its growth. In this study, an envelope glycoprotein, Gn, was targeted. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Inhibitors are herein proposed to negate its action mechanism. On the basis of the scaffolds of favipiravir, a FDA compound already used against hantavirus, a library was designed using a 2D fingerprinting approach. Upon molecular docking analysis, the top four docked compounds-(1) favipiravir (-4.5 kcal/mol), (2) N-hydroxy-3-oxo-3, 4-dihydropyrazine-2-carboxamide (-4.7 kcal/mol), (3) N, 5, 6-trimethyl-2-oxo-1H-pyrazine-3-carboxamide (-4.5 kcal/mol), and (4) 3-propyl-1H-pyrazin-2-one (-3.8)-were prioritized on the basis of the lowest binding energies score. Through molecular docking, the best-categorized compound was subjected to molecular dynamics simulation for a 100-ns time span. Molecular dynamics sheds light on each ligand behavior within the active site. Among the four complexes, only favipiravir and 6320122 compound were found to be stable inside the pocket. This is due to the presence of common rings, pyrazine and carboxamide ring, which make a significant interaction with active key residues Furthermore, the MMPB/GBSA binding free energy analysis calculated for all complexes supported the dynamics results by calculating the most stable values for favipiravir complex (-9.9933 and -8.6951 kcal/mol) and for 6320122 compound complex (-13.8675 and -9.3439 kcal/mol), which demonstrated that the selected compounds have a proper binding affinity with the targeted proteins. The hydrogen bond analysis similarly revealed a strong bonding interaction. The results yielded a strong interaction between the enzyme and the inhibitor throughout the simulation; thus, the inhibitor has the potential to become a lead compound and could be subjected to experimental evaluation to unveil their blockage ability.

Dataset Information

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches.

Publications

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches.

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