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

Sweta, Jajoriya; Khandelwal, Ravina; Srinitha, Sivaraj; Pancholi, Rashi; Adhikary, Ritu; Ali, Meer Asif; Nayarisseri, Anuraj; Vuree, Sugunakar

doi:10.31557/apjcp.2019.20.8.2287

Cited by 27 publications

(6 citation statements)

References 55 publications

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“…In the context of the presence of the drug Enasidenib, we performed RUNX1: DNA-docking interactions employing the AML-associated RUNX1 mutants R142K, D171N, R174Q, P176H, R177Q in comparison to wild type (WT) RUNX1. Interestingly, we found that the docking scores of each of the RUNX1 mutants with Enasidenib was better than that with wild-type RUNX1, with R174Q and R177Q mutants having the highest ΔΔG values ( Figure 5C ), similar to that modeled for the docking of Enasidenib with its established target protein IDH2 ( Sweta et al, 2019 ). Thus, we speculate that at least certain cancer-associated mutations in RUNX1B may exhibit the capacity to alter drug binding, and thereby facilitate drug binding to the RUNX1 protein.…”

Section: Resultssupporting

confidence: 59%

In-silico probing of AML related RUNX1 cancer-associated missense mutations: Predicted relationships to DNA binding and drug interactions

Ullah

Zhang

Sharma

et al. 2022

Front. Mol. Biosci.

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The molecular consequences of cancer associated mutations in Acute myeloid leukemia (AML) linked factors are not very well understood. Here, we interrogated the COSMIC database for missense mutations associated with the RUNX1 protein, that is frequently mis-regulated in AML, where we sought to identify recurrently mutated positions at the DNA-interacting interface. Indeed, six of the mutated residues, out of a total 417 residues examined within the DNA binding domain, evidenced reduced DNA association in in silico predictions. Further, given the prominence of RUNX1’s compromised function in AML, we asked the question if the mutations themselves might alter RUNX1’s interaction (off-target) with known FDA-approved drug molecules, including three currently used in treating AML. We identified several AML-associated mutations in RUNX1 that were calculated to enhance RUNX1’s interaction with specific drugs. Specifically, we retrieved data from the COSMIC database for cancer-associated mutations of RUNX1 by using R package “data.table” and “ggplot2” modules. In the presence of DNA and/or drug, we used docking scores and energetics of the complexes as tools to evaluate predicted interaction strengths with RUNX1. For example, we performed predictions of drug binding pockets involving Enasidenib, Giltertinib, and Midostaurin (AML associated), as well as ten different published cancer associated drug compounds. Docking of wild type RUNX1 with these 13 different cancer-associated drugs indicates that wild-type RUNX1 has a lower efficiency of binding while RUNX1 mutants R142K, D171N, R174Q, P176H, and R177Q suggested higher affinity of drug association. Literature evidence support our prediction and suggests the mutation R174Q affects RUNX1 DNA binding and could lead to compromised function. We conclude that specific RUNX1 mutations that lessen DNA binding facilitate the binding of a number of tested drug molecules. Further, we propose that molecular modeling and docking studies for RUNX1 in the presence of DNA and/or drugs enables evaluation of the potential impact of RUNX1 cancer associated mutations in AML.

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Section: Resultssupporting

confidence: 59%

In-silico probing of AML related RUNX1 cancer-associated missense mutations: Predicted relationships to DNA binding and drug interactions

Ullah

Zhang

Sharma

et al. 2022

Front. Mol. Biosci.

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“…A post dock study included energy minimization and Hbond optimization. Simplex Evolution was xed at max steps 300 and neighbor distance faster 1.00 [59][60][61][62][63][64][65]. Nelder Mead Simplex Minimization (using non-grid force eld and H-bond directionality) was applied after the docking to minimize the complex energy of ligand-receptor interaction [66-71].…”

Section: Molecular Dockingmentioning

confidence: 99%

Structure-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation of VEGF inhibitors for the clinical treatment of Ovarian Cancer

et al. 2022

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Vascular Endothelial Growth Factor (VEGF) and its receptor play an important role both in physiologic and pathologic angiogenesis, which is identi ed in ovarian cancer progression and metastasis development. The aim of the present investigation is to identify a potential Vascular Endothelial Growth Factor inhibitor which is playing a crucial role in stimulating the immunosuppressive microenvironment in tumour cells of the ovary and to examine for an effectiveness of identi ed inhibitor for the treatment of ovarian cancer using various in-silico approaches. 12 established VEGF inhibitors were collected from various literature. The compound AEE788 displays the great a nity towards the target protein as a result of docking study. AEE788 was further used for structure-based virtual screening in order to obtain a more structurally similar compound with high a nity. Among the 80 Virtual screened compounds, CID 88265020, explicates much better a nity than established compound AEE788. Based on Molecular Dynamics Simulation, pharmacophore and comparative toxicity analysis of both the best-established compound and the best virtual screened compound displayed a trivial variation in associated properties. The virtual screened compound CID 88265020 have a high a nity with the lowest re-rank score, and holds a huge potential to inhibit the VGFR and can be implemented for prospective future investigations in Ovarian Cancer.

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“…Therefore, researchers develop target-specific SMIs targeting critical malignant pathways. The combination of SMIs with clinical chemotherapy agents may increase treatment efficiency [15,16].…”

Section: Small Molecule Inhibitors In Lymphomamentioning

confidence: 99%

Drugs and Drug Candidates for the Treatment of Lymphoma

Coşkun¹,

Tutar²,

Abay³

et al. 2022

Lymphoma

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Cancer is the biggest health problem worldwide due to its high mortality rate. Lymphoma is defined as a group of malignant diseases that is caused by clonal proliferation of lymphocytes and is classified under two major groups: Hodgkin lymphoma and non-Hodgkin lymphoma. Genetic predisposition and some environmental factors constitute risk factors. Symptoms of the disease include unexplained fever, swelling of lymph glands, swollen abdomen, tiredness, loss of appetite, frequent infections, and weight loss. Positron emission tomography (PET) and computed tomography (CT) scans, along with MRI, are widely used for the diagnosis of lymphoma. Advanced blood and lymph node biopsy tests are used to evaluate treatment effect on blood cells and to confirm the diagnosis of lymphoma, respectively. Current treatment options include chemotherapy, radiotherapy, and bone marrow/stem cell transplantation. Development of new treatment options for cancer medications includes small molecules and monoclonal antibodies for immunotherapy. In addition, the discovery of new phytochemical agents used in complementary and alternative medicine adds perspective to the treatment of lymphoma.

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

Cited by 27 publications

References 55 publications

In-silico probing of AML related RUNX1 cancer-associated missense mutations: Predicted relationships to DNA binding and drug interactions

In-silico probing of AML related RUNX1 cancer-associated missense mutations: Predicted relationships to DNA binding and drug interactions

Structure-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation of VEGF inhibitors for the clinical treatment of Ovarian Cancer

Drugs and Drug Candidates for the Treatment of Lymphoma

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