Design, Synthesis and Bioactivity Evaluation of 4,6-Disubstituted Pyrido[3,2-d]pyrimidine Derivatives as Mnk and HDAC Inhibitors

Xing, Kun; Jian, Zhang; Han, Yu; Tong, Tong; Liú, Dan; Zhao, Liang

doi:10.3390/molecules25184318

Cited by 9 publications

(3 citation statements)

References 18 publications

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“…Frontiers in Chemistry frontiersin.org Frontiers in Chemistry frontiersin.org can be seen that three ligands showed similar patterns of binding to the protein with a small difference in the number of H-bonds. These interaction patterns were also consistent with the results of several studies; H-bond with amino acid MET162 was described by K. Xing et al, and X. Jin et al, (Jin et al, 2019;Xing et al, 2020). Hydrophobic interactions with VAL98, ALA111, LEU168, and LEU212 were reported by S. Wang et al (Wang et al, 2018) On the other hand, the three ligands interacted with the PIM-2 as shown in Figure 4.…”

Section: Figuresupporting

confidence: 90%

Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

et al. 2022

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MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2.

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Section: Figuresupporting

confidence: 90%

Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

et al. 2022

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“…Among the different DTQ analogues, compound ( 4 ) showed the most promising results, that may be due to the addition of 4-fluoroaniline. In fact, adding 4-fluoroaniline can increase the hydrophobicity, bulkiness and anti-proliferative activity of the compound [ 18 , 51 ]. Yet to confirm the findings, in vitro experimental analysis is warranted.…”

Section: Resultsmentioning

confidence: 99%

Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID

Moin

Huwaimel

Alobaida

et al. 2022

Life

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The COVID-19 era has prompted several researchers to search for a linkage between COVID-19 and its associated neurological manifestation. Toll-like receptor 4 (TLR-4) acts as one such connecting link. spike protein of SARS-CoV-2 can bind either to ACE-2 receptors or to TLR-4 receptors, leading to aggregation of α-synuclein and neurodegeneration via the activation of various cascades in neurons. Recently, dithymoquinone has been reported as a potent multi-targeting candidate against SARS-CoV-2. Thus, in the present study, dithymoquinone and its six analogues were explored to target 3CLpro (main protease of SARS-CoV-2), TLR4 and PREP (Prolyl Oligopeptidases) by using the molecular docking and dynamics approach. Dithymoquinone (DTQ) analogues were designed in order to investigate the effect of different chemical groups on its bioactivity. It is noteworthy to mention that attention was given to the feasibility of synthesizing these analogues by a simple photo-dimerisation reaction. The DTQ analogue containing the 4-fluoroaniline moiety [Compound (4)] was selected for further analysis by molecular dynamics after screening via docking-interaction analyses. A YASARA structure tool built on the AMBER14 force field was used to analyze the 100 ns trajectory by taking 400 snapshots after every 250 ps. Moreover, RMSD, RoG, potential energy plots were successfully obtained for each interaction. Molecular docking results indicated strong interaction of compound (4) with 3CLpro, TLR4 and PREP with a binding energy of −8.5 kcal/mol, −10.8 kcal/mol and −9.5 kcal/mol, respectively, which is better than other DTQ-analogues and control compounds. In addition, compound (4) did not violate Lipinski’s rule and showed no toxicity. Moreover, molecular dynamic analyses revealed that the complex of compound (4) with target proteins was stable during the 100 ns trajectory. Overall, the results predicted that compound (4) could be developed into a potent anti-COVID agent with the ability to mitigate neurological manifestations associated with COVID-19.

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“… 97 Another group designed 4,6-disubstituted pyrido[3,2-d]pyrimidine derivatives that target both MNK and histone deacetylase (HDAC) which inhibited prostate cancer cell growth and could be tested in leukemia cells since HDAC inhibitors are also being explored individually in leukemia. 98 , 99 The effectiveness of these dual inhibitors could be related to the links of MNKs to overcoming resistance as mentioned in the previous section.…”

Section: Preclinical Combination Studies Using Mnk Inhibitorsmentioning

confidence: 99%

MNK Proteins as Therapeutic Targets in Leukemia

Mazewski¹,

Platanias²

2023

OTT

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In leukemia, resistance to therapy is a major concern for survival. MAPK-interacting kinases (MNKs) have been identified as important activators of oncogenic-related signaling and may be mediators of resistance. Recent studies in leukemia models, especially acute myeloid leukemia (AML), have focused on targeting MNKs together with other inhibitors or treating chemotherapy-resistant cells with MNK inhibitors. The preclinical demonstrations of the efficacy of MNK inhibitors in these combination formats would suggest a promising potential for use in clinical trials. Optimizing MNK inhibitors and testing in leukemia models is actively being pursued and may have important implications for the future. These studies are furthering the understanding of the mechanisms of MNKs in cancer which could translate to clinical studies.

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Design, Synthesis and Bioactivity Evaluation of 4,6-Disubstituted Pyrido[3,2-d]pyrimidine Derivatives as Mnk and HDAC Inhibitors

Cited by 9 publications

References 18 publications

Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID

MNK Proteins as Therapeutic Targets in Leukemia

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