Potential inhibitors of the enzyme acetylcholinesterase and juvenile hormone with insecticidal activity: study of the binding mode via docking and molecular dynamics simulations

Ramos, Ryan da Silva; Macêdo, Williams Jorge da Cruz; Costa, Josivan da Silva; Silva, Carlos H. T. de P. da; Rosa, Joaquín M C; Cruz, Jorddy Neves; Oliveira, Mozaniel Santana de; Andrade, Eloísa Helena de Aguiar; Silva, Raullyan B L E; Souto, Raimundo Nonato Picanço; Santos, Cleydson Breno Rodrigues dos

doi:10.1080/07391102.2019.1688192

Cited by 56 publications

(48 citation statements)

References 94 publications

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“…Per-residue free energy decomposition was decomposed using the approach of MM/GBSA according to the following equation [ 14 , 81 , 82 ]: ΔG MM-GBSA = ΔE vdW + ΔE elec + ΔE pol + ΔE np . …”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…In this initial stage, the pivot molecule rofecoxib was used as a research model for the virtual screening in six commercial molecule databases: Chembridge DIVERSetEXP, DIVERSet CORE Library ( ) [ 24 ], Maybridge Collections ( ) [ 25 , 26 ], ZINC Drug Database, ZINC Natural Stock ( ) [ 27 ], and Drug FDA BindingDB ( ) [ 27 ] using the programs Rapid Overlay of Chemical Structures (ROCS) and electrostatic similarity (EON).…”

Section: Resultsmentioning

confidence: 99%

Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach

et al. 2020

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The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = −11.0 kcal/mol), LMQC36 (∆G = −10.6 kcal/mol), and LMQC50 (∆G = −10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = −10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = −45.31 kcal/mol; LMQC72: ΔGbind = −38.58 kcal/mol; LMQC36: ΔGbind = −36.10 kcal/mol; and LMQC50: ΔGbind = −39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.

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“…The pharmacophore features of the selected compounds were generated through the PharmaGist Webserver (https://bioinfo3d.cs.tau.ac.il/PharmaGist/). Detailed information on pharmacophore modeling and structure-based virtual screening have been described elsewhere [47][48][49].…”

Section: Computational Resourcesmentioning

confidence: 99%

“…The predictions of biological activities of the selected compounds were performed while using the PASS webserver http://www.pharmaexpert.ru/passonline [54]. The PASS analysis allows us to discover the effects of a compound based entirely on the molecular formula while using MNA (multilevel neighbors of atoms) descriptors, which suggested that the biological activity is the function of its chemical structure [49,55].…”

Section: Biological Activity Predictions Of the Compoundsmentioning

confidence: 99%

Virtual Screening Approach to Identify High-Affinity Inhibitors of Serum and Glucocorticoid-Regulated Kinase 1 among Bioactive Natural Products: Combined Molecular Docking and Simulation Studies

et al. 2020

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Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that works under acute transcriptional control by several stimuli, including serum and glucocorticoids. It plays a significant role in the cancer progression and metastasis, as it regulates inflammation, apoptosis, hormone release, neuro-excitability, and cell proliferation. SGK1 has recently been considered as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In the present study, we have performed structure-based virtual high-throughput screening of natural compounds from the ZINC database to find potential inhibitors of SGK1. Initially, hits were selected based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and other drug-like properties. Afterwards, PAINS filter, binding affinities estimation, and interaction analysis were performed to find safe and effective hits. We found four compounds bearing appreciable binding affinity and specificity towards the binding pocket of SGK1. The docking results were complemented by all-atom molecular dynamics simulation for 100 ns, followed by MM/PBSA, and principal component analysis to investigate the conformational changes, stability, and interaction mechanism of SGK1 in-complex with the selected compound ZINC00319000. Molecular dynamics simulation results suggested that the binding of ZINC00319000 stabilizes the SGK1 structure, and it leads to fewer conformational changes. In conclusion, the identified compound ZINC00319000 might be further exploited as a scaffold to develop promising inhibitors of SGK1 for the therapeutic management of associated diseases, including cancer.

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Potential inhibitors of the enzyme acetylcholinesterase and juvenile hormone with insecticidal activity: study of the binding mode via docking and molecular dynamics simulations

Cited by 56 publications

References 94 publications

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

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

Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach

Virtual Screening Approach to Identify High-Affinity Inhibitors of Serum and Glucocorticoid-Regulated Kinase 1 among Bioactive Natural Products: Combined Molecular Docking and Simulation Studies

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