Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is symbolized by an increase in the number of myeloid cells in the bone marrow andan arrest in their maturation, frequently resulting in hematopoietic insufficiency (granulocytopenia, thrombocytopenia,or anemia) with or without leukocytosis either by a predominance of immature forms or a loss of normal hematopoiesis.IDH2 gene encodes for isocitrate dehydrogenase enzyme which is involved in the TCA cycle domino effect andconverts isocitrate to alpha-ketoglutarate. In the U.S, the annual incidence of AML progressively increases with ageto a peak of 12.6 per 100,000 adults of 65 years or older. Mutations in isocitrate dehydrogenase 2 (arginine 132) havebeen demonstrated to be recurrent gene alterations in acute myeloid leukemia (AML) by forming 2-Hydroxy alphaketoglutarate which, instead of participating in TCA cycle, accumulates to form AML. The current study approachesby molecular docking and virtual screening to elucidate inhibitor with superior affinity against IDH2 and achieve apharmacological profile. To obtain the best established drug Molegro Virtual Docker algorithm was executed. Thecompound AG-221 (Pub CID 71299339) having the high affinity score was subjected to similarity search to retrievethe drugs with similar properties. The virtual screened compound SCHEMBL16391748 (PubChem CID-117816179)shows high affinity for the protein. Comparative study and ADMET study for both the above compounds resulted inequivalent chemical properties. Virtual screened compound SCHEMBL16391748 (PubChem CID-117816179) showsthe lowest re-rank score. These drugs are identified as high potential IDH2 inhibitors and can halt AML when validatedthrough further In vitro screening.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Asian Pacific journal of cancer prevention : APJCP - 20(2019), 8 vom: 01. Aug., Seite 2287-2297 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sweta, Jajoriya [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 24.01.2020 Date Revised 12.08.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.31557/APJCP.2019.20.8.2287 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM300605307 |
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| 100 | 1 | |a Sweta, Jajoriya |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia |
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| 500 | |a Date Revised 12.08.2022 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Acute myeloid leukemia (AML) is symbolized by an increase in the number of myeloid cells in the bone marrow andan arrest in their maturation, frequently resulting in hematopoietic insufficiency (granulocytopenia, thrombocytopenia,or anemia) with or without leukocytosis either by a predominance of immature forms or a loss of normal hematopoiesis.IDH2 gene encodes for isocitrate dehydrogenase enzyme which is involved in the TCA cycle domino effect andconverts isocitrate to alpha-ketoglutarate. In the U.S, the annual incidence of AML progressively increases with ageto a peak of 12.6 per 100,000 adults of 65 years or older. Mutations in isocitrate dehydrogenase 2 (arginine 132) havebeen demonstrated to be recurrent gene alterations in acute myeloid leukemia (AML) by forming 2-Hydroxy alphaketoglutarate which, instead of participating in TCA cycle, accumulates to form AML. The current study approachesby molecular docking and virtual screening to elucidate inhibitor with superior affinity against IDH2 and achieve apharmacological profile. To obtain the best established drug Molegro Virtual Docker algorithm was executed. Thecompound AG-221 (Pub CID 71299339) having the high affinity score was subjected to similarity search to retrievethe drugs with similar properties. The virtual screened compound SCHEMBL16391748 (PubChem CID-117816179)shows high affinity for the protein. Comparative study and ADMET study for both the above compounds resulted inequivalent chemical properties. Virtual screened compound SCHEMBL16391748 (PubChem CID-117816179) showsthe lowest re-rank score. These drugs are identified as high potential IDH2 inhibitors and can halt AML when validatedthrough further In vitro screening | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a IDH2 | |
| 650 | 4 | |a Molecular docking | |
| 650 | 4 | |a Virtual screening | |
| 650 | 4 | |a acute myeloid leukemia | |
| 650 | 7 | |a Aminopyridines |2 NLM | |
| 650 | 7 | |a Small Molecule Libraries |2 NLM | |
| 650 | 7 | |a Triazines |2 NLM | |
| 650 | 7 | |a enasidenib |2 NLM | |
| 650 | 7 | |a 3T1SS4E7AG |2 NLM | |
| 650 | 7 | |a IDH2 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.1.1.41 |2 NLM | |
| 650 | 7 | |a Isocitrate Dehydrogenase |2 NLM | |
| 650 | 7 | |a EC 1.1.1.41 |2 NLM | |
| 700 | 1 | |a Khandelwal, Ravina |e verfasserin |4 aut | |
| 700 | 1 | |a Srinitha, Sivaraj |e verfasserin |4 aut | |
| 700 | 1 | |a Pancholi, Rashi |e verfasserin |4 aut | |
| 700 | 1 | |a Adhikary, Ritu |e verfasserin |4 aut | |
| 700 | 1 | |a Ali, Meer Asif |e verfasserin |4 aut | |
| 700 | 1 | |a Nayarisseri, Anuraj |e verfasserin |4 aut | |
| 700 | 1 | |a Vuree, Sugunakar |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Sanjeev Kumar |e verfasserin |4 aut | |
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