Molecular dynamics simulation and QM/MM calculation reveal the selectivity mechanism of type I 1/2 kinase inhibitors: the effect of intramolecular H-bonds and conformational restriction for improved selectivity

Wang, Hanxun; Gao, Zisen; Song, Peilu; Hu, Baichun; Wang, Jian

doi:10.1039/c9cp04353e

Cited by 25 publications

(9 citation statements)

References 47 publications

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“…It was usually based on the hypothesis that the main chain conformation did not modify and the side chains beyond the β-carbon for ligand-protein complexes were reduced after substituting an amino acid residue into alanine. As reported, ASM analysis has been regarded as an appealing alternative to in vitro experiments [ 45 , 46 ]. In this study, ASM analysis was used to validate the binding free energy decomposition analysis.…”

Section: Resultsmentioning

confidence: 99%

“…ASM analysis was usually used to investigate the role of a specific amino acid residue participating in protein-protein or protein-ligand interactions [ 45 , 46 ]. It was applied to further validate the binding free energy decomposition analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The difference between the binding free energies for the wild type (ΔG bind,wild type ) and the mutant (ΔG bind,mutant ) yield the changes of binding free energy (ΔΔG bind ) arising from the substitution of a specific amino acid by an alanine. More positive ΔΔG bind value indicates that the single mutation caused more significant effects and this specific residue played an important role in ligand binding [ 45 , 46 ].…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents

Zhang

Tang

Meng

et al. 2022

IJMS

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In this study, a series of 4-[(quinolin-4-yl)amino]benzamide derivatives as the novel anti-influenza agents were designed and synthesized. Cytotoxicity assay, cytopathic effect assay and plaque inhibition assay were performed to evaluate the anti-influenza virus A/WSN/33 (H1N1) activity of the target compounds. The target compound G07 demonstrated significant anti-influenza virus A/WSN/33 (H1N1) activity both in cytopathic effect assay (EC50 = 11.38 ± 1.89 µM) and plaque inhibition assay (IC50 = 0.23 ± 0.15 µM). G07 also exhibited significant anti-influenza virus activities against other three different influenza virus strains A/PR/8 (H1N1), A/HK/68 (H3N2) and influenza B virus. According to the result of ribonucleoprotein reconstitution assay, G07 could interact well with ribonucleoprotein with an inhibition rate of 80.65% at 100 µM. Furthermore, G07 exhibited significant activity target PA−PB1 subunit of RNA polymerase according to the PA−PB1 inhibitory activity prediction by the best pharmacophore Hypo1. In addition, G07 was well drug-likeness based on the results of Lipinski’s rule and ADMET prediction. All the results proved that 4-[(quinolin-4-yl)amino]benzamide derivatives could generate potential candidates in discovery of anti-influenza virus agents.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents

Zhang

Tang

Meng

et al. 2022

IJMS

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“…The Hsp90 crystal structure (PDB code: 6CJL, 6CJP), which was downloaded from the protein data bank (), was processed with the Protein Preparation Wizard in the Schrödinger suite. , The protein structure was adjusted and modified, followed by adding hydrogen atoms, deleting solvent water molecules, and defining right bonds orders using Prime. The protonation and tautomeric states of Asp, Lys, and His were assigned at the pH 7.4 state.…”

Section: Methodsmentioning

confidence: 99%

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Yin

Liu

et al. 2022

J. Med. Chem.

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Invasive fungal infections are emerging as serious infectious diseases worldwide. Because of the development of antifungal drug resistance, the limited efficacy of the existing drugs has led to high mortality in patients. The use of the essential eukaryotic chaperone Hsp90, which plays a multifaceted role in drug resistance across diverse pathogenic fungal species, is considered to be a new strategy to mitigate the resistance and counter the threat posed by drug-resistant fungi. Thus, a series of 4,5diarylisoxazole analogues as fungal Hsp90 inhibitors were designed and synthesized that had potent synergistic effects with fluconazole in vitro and in vivo. In particular, compound A17 could avoid the potential mammalian toxicity of Hsp90 inhibitors based on key reside differences between humans and fungi. These data support the feasibility of targeting fungal Hsp90 as a promising antifungal strategy and further development of compound A17 as a valuable research probe for the investigation of fungal Hsp90.

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“…This allows an in-depth estimation of the thermodynamics and kinetics related to drug-target recognition and binding [ 18 ]. MD simulations have been extensively used in the study of protein-protein and protein-ligand interactions, and the study of the mechanism of drug action [ 19 , 20 , 21 , 22 , 23 ]. The plethora of applications of molecular dynamics simulations extend from the study of complex and dynamic processes that play a central role in biological systems to the structure determination from X-ray crystallography and NMR experiments.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations in Designing DARPins as Phosphorylation-Specific Protein Binders of ERK2

et al. 2021

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Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. Here, we report a class of repeat proteins—designed ankyrin repeat protein (DARPin) macromolecules targeting ERK2 as inhibitors. The structural basis of ERK2–DARPin interactions based on molecular dynamics (MD) simulations was studied. The information was then used to predict stabilizing mutations employing a web-based algorithm, MAESTRO. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations. Two mutations, Ala → Asp and Ser → Leu, were found to perform better than the original sequence (DARPin E40) based on the associated energy and key residues involved in protein-protein interaction. MD simulations and analysis of the data obtained on these mutations supported our predictions.

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Molecular dynamics simulation and QM/MM calculation reveal the selectivity mechanism of type I 1/2 kinase inhibitors: the effect of intramolecular H-bonds and conformational restriction for improved selectivity

Abstract: Multi-selectivity mechanisms of propynol inhibitors against NIK or PAK4 were reviewed using molecular dynamics, DFT and other atomistic simulations.

Cited by 25 publications

References 47 publications

Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents

Design, Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents

Species-Selective Targeting of Fungal Hsp90: Design, Synthesis, and Evaluation of Novel 4,5-Diarylisoxazole Derivatives for the Combination Treatment of Azole-Resistant Candidiasis

Molecular Dynamics Simulations in Designing DARPins as Phosphorylation-Specific Protein Binders of ERK2

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