Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

Document Type: Research Articles

Authors

1 In silico Research Laboratory, Eminent Biosciences, Vijaynagar, Indore- 452010, Madhya Pradesh, India.

2 Bioinformatics Research Laboratory, LeGene Biosciences Pvt Ltd, Mahalakshmi Nagar, Indore-452010, Madhya Pradesh, India.

3 Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 003, Tamil Nadu, India.

4 Department of Biotechnology, Lovely Faculty of Technology and Sciences, Division of Research and Development, Lovely Professional University, Phagwara, Punjab, India.

Abstract

Acute myeloid leukemia (AML) is symbolized by an increase in the number of myeloid cells in the bone marrow and
an 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 and
converts isocitrate to alpha-ketoglutarate. In the U.S, the annual incidence of AML progressively increases with age
to a peak of 12.6 per 100,000 adults of 65 years or older. Mutations in isocitrate dehydrogenase 2 (arginine 132) have
been demonstrated to be recurrent gene alterations in acute myeloid leukemia (AML) by forming 2-Hydroxy alpha
ketoglutarate which, instead of participating in TCA cycle, accumulates to form AML. The current study approaches
by molecular docking and virtual screening to elucidate inhibitor with superior affinity against IDH2 and achieve a
pharmacological profile. To obtain the best established drug Molegro Virtual Docker algorithm was executed. The
compound AG-221 (Pub CID 71299339) having the high affinity score was subjected to similarity search to retrieve
the 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 in
equivalent chemical properties. Virtual screened compound SCHEMBL16391748 (PubChem CID-117816179) shows
the lowest re-rank score. These drugs are identified as high potential IDH2 inhibitors and can halt AML when validated
through further In vitro screening.

Keywords

Main Subjects