Design, synthesis, in vitro anticancer and antimicrobial evaluation, SAR analysis, molecular docking and dynamic simulation of new pyrazoles, triazoles and pyridazines based isoxazole

Radwan, Hyam A.; Ahmad, Iqrar; Othman, Ismail M.M.; Gad‐Elkareem, Mohamed A. M.; Patel, Harun; Snoussi, Mejdi; Kadri, Adel

doi:10.1016/j.molstruc.2022.133312

Cited by 46 publications

(17 citation statements)

References 53 publications

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“…Molecular dynamics (MD) studies were carried out utilizing an NVIDIA Quadro 6000 graphics processing unit and the Desmond MD simulation software for the docking poses of CA4 in the hMAO-B enzyme with the lowest negative score, i.e., top-docking poses. − As earlier studies, more information for MD investigations such as thermostat and barometer settings, box type, short- and long-range interaction calculations was considered because the same settings were applied for the analyzed systems here, i.e., 100 ns of MD generation was done, with coordinates stored at 100 ps to produce trajectories of 1000 frames each for investigating the dynamics of protein–ligand interactions. − Finally, the simulated interaction diagram tool was used for stability analysis.…”

Section: Methodsmentioning

confidence: 99%

“… 41 − 44 As earlier studies, more information for MD investigations such as thermostat and barometer settings, box type, short- and long-range interaction calculations was considered because the same settings were applied for the analyzed systems here, i.e., 100 ns of MD generation was done, with coordinates stored at 100 ps to produce trajectories of 1000 frames each for investigating the dynamics of protein–ligand interactions. 45 − 49 Finally, the simulated interaction diagram tool was used for stability analysis.…”

Section: Methodsmentioning

confidence: 99%

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Development of Isopropyl-Tailed Chalcones as a New Class of Selective MAO-B Inhibitors for the Treatment of Parkinson’s Disorder

Abdelgawad

Abourehab

et al. 2023

ACS Omega

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Thirteen isopropyl chalcones (CA1−CA13) were synthesized and evaluated for their inhibitory activity against monoamine oxidase (MAO). All compounds inhibited MAO-B more effectively than MAO-A. Compound CA4 most potently inhibited MAO-B with an IC 50 value of 0.032 μM, similar to that of CA3 (IC 50 = 0.035 μM) and with high selectivity index (SI) values for MAO-B over respectively). The −OH (CA4) or −F (CA3) group at the para position on the A ring provided higher MAO-B inhibition than that of the other substituents (−OH ≥ −F > −Cl > −Br > −OCH 2 CH 3 > −CF 3 ). On the other hand, compound CA10 most potently inhibited MAO-A with an IC 50 value of 0.310 μM and effectively MAO-B (IC 50 = 0.074 μM). The Br-containing thiophene substituent (CA10) instead of the A ring showed the highest MAO-A inhibition. In a kinetic study, K i values of compounds CA3 and CA4 for MAO-B were 0.076 ± 0.001 and 0.027 ± 0.002 μM, respectively, and that of CA10 for MAO-A was 0.016 ± 0.005 μM. A reversibility study showed that CA3 and CA4 were reversible inhibitors of MAO-B and CA10 was a reversible inhibitor of MAO-A. In docking and molecular dynamics, the hydroxyl group of CA4 and two hydrogen bonds contributed to the stability of the protein−ligand complex. These results suggest that CA3 and CA4 are potent reversible selective MAO-B inhibitors and can be used for the treatment of Parkinson's disease.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Development of Isopropyl-Tailed Chalcones as a New Class of Selective MAO-B Inhibitors for the Treatment of Parkinson’s Disorder

Abdelgawad

Abourehab

et al. 2023

ACS Omega

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“…The constructed system was then subjected to energy minimization using preset OPLS3e force field parameters to accurately align the protein structure within the simulation constraints and to minimize electronic conflicts between protein structures [ 41 , 42 ]. The energy-minimized system was then put through a 50 ns MD simulation with an “isothermal-isobaric ensemble” (NPT) employing a 1 bar using Martyna–Tobias–Klein barostats and a Nose–Hoover thermostat at 300 K [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

Virtual Screening for Identification of Dual Inhibitors against CDK4/6 and Aromatase Enzyme

et al. 2023

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CDK4/6 and aromatase are prominent targets for breast cancer drug discovery and are involved in abnormal cell proliferation and growth. Although aromatase inhibitors have proven to be effective (for example exemestane, anastrozole, letrozole), resistance to treatment eventually occurs through the activation of alternative signaling pathways, thus evading the antiproliferative effects of aromatase inhibitors. One of the evasion pathways is Cylin D-CDK4/6-Rb signaling that promotes tumor proliferation and resistance to aromatase inhibitors. There is significant evidence that the sequential inhibition of both proteins provides therapeutic benefits over the inhibition of one target. The basis of this study objective is the identification of molecules that are likely to inhibit both CDK4/6 and aromatase by computational chemistry techniques, which need further biochemical studies to confirm. Initially, a structure-based pharmacophore model was constructed for each target to screen the sc-PDB database. Consequently, pharmacophore screening and molecular docking were performed to evaluate the potential lead candidates that effectively mapped both of the target pharmacophore models. Considering abemaciclib (CDK4/6 inhibitor) and exemestane (aromatase inhibitor) as reference drugs, four potential virtual hit candidates (1, 2, 3, and 4) were selected based on their fit values and binding interaction after screening a sc-PDB database. Further, molecular dynamics simulation studies solidify the stability of the lead candidate complexes. In addition, ADMET and DFT calculations bolster the lead candidates. Hence, these combined computational approaches will provide a better therapeutic potential for developing CDK4/6-aromatase dual inhibitors for HR+ breast cancer therapy.

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“…One of the essential metrics that describes fluctuations in structural conformation of the protein backbone over time during system equilibration is the RMSD value acquired from the MD simulation trajectory, and low and consistent RMSD values show the protein structure's stability. To analyze the ligand-protein interaction, the protein should approach equilibrium, that is, the RMSD value should remain steady [80][81][82] . Figure 6 shows the RMSD computed for the two complexes based on the protein backbone using the Simulation interaction diagram tool.…”

Section: Simulationmentioning

confidence: 99%

Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors

Sudevan

Abdelgawad

et al. 2022

Sci Rep

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The inhibitory action of fifteen benzyloxy ortho/para-substituted chalcones (B1-B15) was evaluated against human monoamine oxidases (hMAOs). All the molecules inhibited hMAO-B isoform more potently than hMAO-A. Furthermore, the majority of the molecules showed strong inhibitory actions against hMAO-B at 10 μM level with residual activities of less than 50%. Compound B10 has an IC50 value of 0.067 μM, making it the most potent inhibitor of hMAO-B, trailed by compound B15 (IC50 = 0.12 μM). The thiophene substituent (B10) in the A-ring exhibited the strongest hMAO-B inhibition structurally, however, increased residue synthesis did not result in a rise in hMAO-B inhibition. In contrast, the benzyl group at the para position of the B-ring displayed more hMAO-B inhibition than the other positions. Compounds B10 and B15 had relatively high selectivity index (SI) values for hMAO-B (504.791 and 287.600, respectively). Ki values of B10 and B15 were 0.030 ± 0.001 and 0.033 ± 0.001 μM, respectively. The reversibility study showed that B10 and B15 were reversible inhibitors of hMAO-B. PAMPA assay manifested that the benzyloxy chalcones (B10 and B15) had a significant permeability and CNS bioavailability with Pe value higher than 4.0 × 10–6 cm/s. Both compounds were stabilized in protein–ligand complexes by the π-π stacking, which enabled them to bind to the hMAO-B enzyme's active site incredibly effectively. The hMAO-B was stabilized by B10- and B15-hMAO-B complexes, with binding energies of − 74.57 and − 87.72 kcal/mol, respectively. Using a genetic algorithm and multiple linear regression, the QSAR model was created. Based on the best 2D and 3D descriptor-based QSAR model, the following statistics were displayed: R2 = 0.9125, Q2loo = 0.8347. These findings imply that B10 and B15 are effective, selective, and reversible hMAO-B inhibitors.

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Design, synthesis, in vitro anticancer and antimicrobial evaluation, SAR analysis, molecular docking and dynamic simulation of new pyrazoles, triazoles and pyridazines based isoxazole

Cited by 46 publications

References 53 publications

Development of Isopropyl-Tailed Chalcones as a New Class of Selective MAO-B Inhibitors for the Treatment of Parkinson’s Disorder

Development of Isopropyl-Tailed Chalcones as a New Class of Selective MAO-B Inhibitors for the Treatment of Parkinson’s Disorder

Virtual Screening for Identification of Dual Inhibitors against CDK4/6 and Aromatase Enzyme

Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors

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