Insights into features and lead optimization of novel type 1½ inhibitors of p38α mitogen-activated protein kinase using QSAR, quantum mechanics, bioisostere replacement and ADMET studies

Joel, Ireoluwa Yinka; Adigun, Temidayo Olamide; Bankole, Olukayode Olusola; Iduze, Mohammed Aminu; AbelJack-Soala, Tamonokorite; Ani, Onyedika Gabriel; Olapade, Elijah Oluwafunto; Dada, Friday Micheal; Adetiwa, Olusola Mercy; Ofeniforo, Bankole Emmanuel; Akanni, Funmilola Olamide

doi:10.1016/j.rechem.2020.100044

Cited by 8 publications

(7 citation statements)

References 20 publications

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“…In the gas phase, electronic characterization of the synthesized compounds was carried out using Becke's three parameter exchange‐functional (B3) in combination with the gradient‐corrected correlation functional of Lee, Yang, and Parr (LYP). Frequency calculations were used to validate the optimization, and the absence of imaginary frequencies revealed minimum energy for the structures [45] . Taking these optimized structures HOMO‐LUMO energies (electronic parameters such as ionization potential, electronegativity, electrophilic index, nucleophilic index, and chemical potential obtained from these energies), MESP analysis was conducted using the same method.…”

Section: Methodsmentioning

confidence: 99%

“…Frequency calculations were used to validate the optimization, and the absence of imaginary frequencies revealed minimum energy for the structures. [45] Taking these optimized structures HOMO-LUMO energies (electronic parameters such as ionization potential, electronegativity, electrophilic index, nucleophilic index, and chemical potential obtained from these energies), MESP analysis was conducted using the same method. The Jaguar software was used to execute the Quantum computations, and the maestro interface was utilized to analyze the molecular orbitals.…”

Section: Quantum Chemistry Computationsmentioning

confidence: 99%

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Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 1,3,4‐Thiadiazole Derivatives as Potent Antimicrobial Agents

Çevik

Çeli̇k

İnce

et al. 2023

Chemistry & Biodiversity

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In this work, the synthesis, characterization, and biological activities of a new series of 1,3,4-thiadiazole derivatives were investigated. The structures of final compounds were identified using 1 H-NMR, 13 C-NMR, elemental analysis, and HRMS. All the new synthesized compounds were then screened for their antimicrobial activity against four types of pathogenic bacteria and one fungal strain, by application of the MIC assays, using Ampicilin, Gentamycin, Vancomycin, and Fluconazole as standards. Among the compounds, the MIC values of 4 and 8 μg/mL of the compounds 3f and 3g, respectively, are remarkable and indicate that these compounds are good candidates for antifungal activity. The docking experiments were used to identify the binding forms of produced ligands with sterol 14-demethylase to acquire insight into relevant proteins. The MD performed about 100 ns simulations to validate selected compounds' theoretical studies. Finally, using density functional theory (DFT) to predict reactivity, the chemical characteristics and quantum factors of synthesized compounds were computed. These results were then correlated with the experimental data. Furthermore, computational estimation was performed to predict the ADME properties of the most active compound 3f.

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Section: Methodsmentioning

confidence: 99%

Section: Quantum Chemistry Computationsmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 1,3,4‐Thiadiazole Derivatives as Potent Antimicrobial Agents

Çevik

Çeli̇k

İnce

et al. 2023

Chemistry & Biodiversity

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“…Bio-isostere replacement tool from maestro software was used to replace the different functional groups with selected compounds for better potency and pharmacokinetic profiles. Hence, generated bio-isosteres results were analyzed through a ligand interaction with amino acid residues, XP-docking score, binding energy, and ADME analysis (Joel et al 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Amelioration of high-fat diet (HFD) + CCl4 induced NASH/NAFLD in CF-1 mice by activation of SIRT-1 using cinnamoyl sulfonamide hydroxamate derivatives: in-silico molecular modelling and in-vivo prediction

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) is one of the major hepatic metabolic disorders that occurs because of the accumulation of lipids in hepatocytes in the form of free fatty acids (FFA) and triglycerides (TG) which become non-alcoholic steatohepatitis (NASH). NOTCH-1 receptors act as novel targets for the development of NAFLD/NASH, where overexpression of NOTCH-1 receptor alters the lipid metabolism in hepatocytes leading to NAFLD. SIRT-1 deacetylates the NOTCH-1 receptor and inhibits NAFLD. Hence, computer-aided drug design (CADD) was used to check the SIRT-1 activation ability of cinnamic sulfonyl hydroxamate derivatives (NMJ 1–8), resveratrol, and vorinostat. SIRT-1 (PDB ID: 5BTR) was docked with eight hydroxamate derivatives and vorinostat using Schrödinger software. Based on binding energy obtained (– 26.31 to – 47.34 kcal/mol), vorinostat, NMJ-2, NMJ-3, NMJ-5 were selected for induced-fit docking (IFD) and results were within – 750.70 to – 753.22 kcal/mol. Qikprop tool was used to analyse the pre pharmacokinetic parameters (ADME analysis) of all hydroxamate compounds. As observed in the molecular dynamic (MD) study, NMJ-2, NMJ-3 were showing acceptable results for activation of SIRT-1. Based on these predictions, in-vivo studies were conducted in CF1 mice, where NMJ-3 showed significant (p < 0.05) changes in lipid profile and anti-oxidant parameters (Catalase, SOD, GSH, nitrite, and LPO) and plasma insulin levels. NMJ-3 treatment also reduced inflammation, fibrosis, and necrosis in liver samples.

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“…However, before any model can be used in practice, the reliability of its application must be confirmed by different validation procedures [31]. In this study, the GBT-based mixed model was validated via tenfold crossvalidation and, in addition, by an external validation set.…”

Section: Qspr Modelingmentioning

confidence: 99%

Charged aerosol detector response modeling for fatty acids based on experimental settings and molecular features: a machine learning approach

et al. 2021

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The charged aerosol detector (CAD) is the latest representative of aerosol-based detectors that generate a response independent of the analytes’ chemical structure. This study was aimed at accurately predicting the CAD response of homologous fatty acids under varying experimental conditions. Fatty acids from C12 to C18 were used as model substances due to semivolatile characterics that caused non-uniform CAD behaviour. Considering both experimental conditions and molecular descriptors, a mixed quantitative structure–property relationship (QSPR) modeling was performed using Gradient Boosted Trees (GBT). The ensemble of 10 decisions trees (learning rate set at 0.55, the maximal depth set at 5, and the sample rate set at 1.0) was able to explain approximately 99% (Q2: 0.987, RMSE: 0.051) of the observed variance in CAD responses. Validation using an external test compound confirmed the high predictive ability of the model established (R2: 0.990, RMSEP: 0.050). With respect to the intrinsic attribute selection strategy, GBT used almost all independent variables during model building. Finally, it attributed the highest importance to the power function value, the flow rate of the mobile phase, evaporation temperature, the content of the organic solvent in the mobile phase and the molecular descriptors such as molecular weight (MW), Radial Distribution Function—080/weighted by mass (RDF080m) and average coefficient of the last eigenvector from distance/detour matrix (Ve2_D/Dt). The identification of the factors most relevant to the CAD responsiveness has contributed to a better understanding of the underlying mechanisms of signal generation. An increased CAD response that was obtained for acetone as organic modifier demonstrated its potential to replace the more expensive and environmentally harmful acetonitrile.

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Insights into features and lead optimization of novel type 1½ inhibitors of p38α mitogen-activated protein kinase using QSAR, quantum mechanics, bioisostere replacement and ADMET studies

Cited by 8 publications

References 20 publications

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 1,3,4‐Thiadiazole Derivatives as Potent Antimicrobial Agents

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 1,3,4‐Thiadiazole Derivatives as Potent Antimicrobial Agents

Amelioration of high-fat diet (HFD) + CCl4 induced NASH/NAFLD in CF-1 mice by activation of SIRT-1 using cinnamoyl sulfonamide hydroxamate derivatives: in-silico molecular modelling and in-vivo prediction

Charged aerosol detector response modeling for fatty acids based on experimental settings and molecular features: a machine learning approach

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