Targeting hPKM2 in cancer: A bio isosteric approach for ligand design

Pipitò, Ludovico; Illingworth, Thomas Arron; Deganutti, Giuseppe

doi:10.1016/j.compbiomed.2023.106852

Cited by 5 publications

(1 citation statement)

References 57 publications

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“…We used a 9 Å cutoff distance and a 7.5 Å switching distance for the van der Waals and electrostatic forces. These parameters are the default values in ACEMD3, and the same choice can be seen in a variety of MD simulation studies on several different systems by a variety of investigators − as well as in our previous studies of thrombin. − …”

Section: Methodsmentioning

confidence: 99%

Unraveling the Role of Hydrogen Bonds in Thrombin via Two Machine Learning Methods

Salsbury

2023

J. Chem. Inf. Model.

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Hydrogen bonds play a critical role in the folding and stability of proteins, such as proteins and nucleic acids, by providing strong and directional interactions. They help to maintain the secondary and 3D structure of proteins, and structural changes in these molecules often result from the formation or breaking of hydrogen bonds. To gain insights into these hydrogen bonding networks, we applied two machine learning models - a logistic regression model and a decision tree model - to study four variants of thrombin: wild-type, ΔK9, E8K, and R4A. Our results showed that both models have their unique advantages. The logistic regression model highlighted potential key residues (GLU295) in thrombin’s allosteric pathways, while the decision tree model identified important hydrogen bonding motifs. This information can aid in understanding the mechanisms of folding in proteins and has potential applications in drug design and other therapies. The use of these two models highlights their usefulness in studying hydrogen bonding networks in proteins.

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Section: Methodsmentioning

confidence: 99%

Unraveling the Role of Hydrogen Bonds in Thrombin via Two Machine Learning Methods

Salsbury

2023

J. Chem. Inf. Model.

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Small Molecule Compound DHPA Screened by Computer-Aided Drug Design and Molecular Dynamics Simulation Inhibits Neuroblastoma Cell Proliferation by Targeting TrkB

Liu,

Yin,

et al. 2024

ACS Omega

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Neuroblastoma (NB) is a rare and malignant pediatric solid tumor. Due to its heterogeneity, it poses significant challenges for treatment, resulting in a high mortality rate. This study aimed to identify new therapeutic drugs by modeling the TrkB receptor from PDB 4AT5 and conducting virtual screening of compounds from the YaTCM database (containing 47,696 compounds derived from 6220 Traditional Chinese Medicines). The screening utilized the E-pharmacophore approach to select compounds with potential binding affinity to TrkB. The binding abilities of these compounds were tested through molecular dynamics simulations, stretch dynamics simulations, and US simulations. Among the top 11 optimized hit compounds, DHPA and 3″-demethylhexahydrocurcumin are prominent. Further simulations reveal that they form stable receptor−ligand binary complexes with TrkB. In subsequent in vitro cell experiments, 3″-demethylhexahydrocurcumin is eliminated due to its high IC 50 for killing NB cells. Low concentrations of DHPA can significantly kill NB cells. Additionally, DHPA can inhibit the expression of TrkB, the activation of TrkB's downstream signaling pathways, and affect the thermal stability of TrkB protein and its response to streptase protease degradation. DHPA may be a potential TrkB inhibitor.

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Lactate exacerbates lung damage induced by nanomicroplastic through the gut microbiota–HIF1a/PTBP1 pathway

Xuan,

Xu,

Luo

et al. 2023

Exp Mol Med

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Exposure to nanomicroplastics (nano-MPs) can induce lung damage. The gut microbiota is a critical modulator of the gut–lung axis. However, the mechanisms underlying these interactions have not been elucidated. This study explored the role of lactate, a key metabolite of the microbiota, in the development of lung damage induced by nano-MPs (LDMP). After 28 days of exposure to nano-MPs (50–100 nm), mice mainly exhibited damage to the lungs and intestinal mucosa and dysbiosis of the gut microbiota. Lactate accumulation was observed in the lungs, intestines and serum and was strongly associated with the imbalance in lactic acid bacteria in the gut. Furthermore, no lactate accumulation was observed in germ-free mice, while the depletion of the gut microbiota using a cocktail of antibiotics produced similar results, suggesting that lactate accumulation in the lungs may have been due to changes in the gut microbiota components. Mechanistically, elevated lactate triggers activation of the HIF1a/PTBP1 pathway, exacerbating nano-MP-induced lung damage through modulation of the epithelial–mesenchymal transition (EMT). Conversely, mice with conditional knockout of Ptbp1 in the lungs (Ptbp1flfl) and PTBP1-knockout (PTBP1-KO) human bronchial epithelial (HBE) cells showed reversal of the effects of lactate through modulation of the HIF1a/PTBP1 signaling pathway. These findings indicate that lactate is a potential target for preventing and treating LDMP.

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Targeting hPKM2 in cancer: A bio isosteric approach for ligand design

Cited by 5 publications

References 57 publications

Unraveling the Role of Hydrogen Bonds in Thrombin via Two Machine Learning Methods

Unraveling the Role of Hydrogen Bonds in Thrombin via Two Machine Learning Methods

Small Molecule Compound DHPA Screened by Computer-Aided Drug Design and Molecular Dynamics Simulation Inhibits Neuroblastoma Cell Proliferation by Targeting TrkB

Lactate exacerbates lung damage induced by nanomicroplastic through the gut microbiota–HIF1a/PTBP1 pathway

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