Small Molecule Inhibitors Targeting Methyltransferase-Like (METTL) Proteins Against Hepatocellular Carcinoma: A Comprehensive Drug Repurposing Approach
ABSTRACT An efficient and durable multi-targeted therapeutic drug against hepatocellular carcinoma (HCC) has recently been a growing concern for tackling the chemoresistance of approved anti-HCC drugs. Recent studies indicated that methyltransferase-like (METTL) proteins including METTL1, METTL3, METTL6, METTL16, and METTL18, have overexpressed and associated with the progression of HCC malignancy, and making them excellent biomarkers. Here, we present a series of bioinformatics study including novel compound repurposing approach, molecular docking, pharmacophore modeling, and molecular dynamic simulation, which revealed two first-in-class highly potent catalytic multi-target inhibitors (ZINC70666503 and ZINC13000658 with 87% and 82% drug scores, respectively) of methyltransferase-like proteins. Comparatively, these two inhibitors showed a notable binding affinity against studied METTL proteins. Furthermore, ADME and toxicity analysis suggested that these two commercially available compounds have good drug-likeliness properties with no potent toxic effects. Of note, the molecular dynamics study supported their conformational stability and high selectivity at the pocket of proteins’ adenosine moiety of S-Adenosyl Methionine. However, this comprehensive analysis needsin vivovalidation to facilitate multi-targeting therapeutic development against hepatocellular carcinoma..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 08. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Morshed, Md Niaz [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.03.11.532187 |
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XBI038938197 |
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| 520 | |a ABSTRACT An efficient and durable multi-targeted therapeutic drug against hepatocellular carcinoma (HCC) has recently been a growing concern for tackling the chemoresistance of approved anti-HCC drugs. Recent studies indicated that methyltransferase-like (METTL) proteins including METTL1, METTL3, METTL6, METTL16, and METTL18, have overexpressed and associated with the progression of HCC malignancy, and making them excellent biomarkers. Here, we present a series of bioinformatics study including novel compound repurposing approach, molecular docking, pharmacophore modeling, and molecular dynamic simulation, which revealed two first-in-class highly potent catalytic multi-target inhibitors (ZINC70666503 and ZINC13000658 with 87% and 82% drug scores, respectively) of methyltransferase-like proteins. Comparatively, these two inhibitors showed a notable binding affinity against studied METTL proteins. Furthermore, ADME and toxicity analysis suggested that these two commercially available compounds have good drug-likeliness properties with no potent toxic effects. Of note, the molecular dynamics study supported their conformational stability and high selectivity at the pocket of proteins’ adenosine moiety of S-Adenosyl Methionine. However, this comprehensive analysis needsin vivovalidation to facilitate multi-targeting therapeutic development against hepatocellular carcinoma. | ||
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| 700 | 1 | |a Saha, Manash Kumar |4 aut | |
| 700 | 1 | |a Fardous, Jannatul |4 aut | |
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