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Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora
Ítalo Antônio Fernandes1, Déborah Braga Resende2, Teodorico Castro Ramalho1,3
1Department of Chemistry, Federal University of Lavras, P.O. Box 3037, Lavras-MG 37200-000, Brazil.
Molecules (Basel, Switzerland)
|April 15, 2020
Summary
Researchers explored indolin-2-one derivatives as potential anticancer drugs, particularly for acute myeloid leukemia (AML). Compound 1 demonstrated superior FLT3 inhibition compared to Sunitinib, with several derivatives showing promise for further development.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Oncology
Background:
- FMS-like tyrosine kinase 3 (FLT3) and dual Aurora B/FLT3 inhibitors are crucial in developing novel anticancer agents, especially for acute myeloid leukemia (AML).
- Indolin-2-one derivatives, structurally related to Sunitinib, are being investigated for their therapeutic potential.
Purpose of the Study:
- To investigate the interaction of human FLT3 kinase domain with novel indolin-2-one derivatives.
- To predict the binding conformations and interaction energies of these compounds using computational methods.
- To identify promising candidates for further synthesis and biological evaluation as anticancer agents.
Main Methods:
- Docking analyses were performed using Molegro Virtual Docker (MVD) software.
- A predictive model was developed using Chemoface, achieving an R-squared value of 0.82 for the training group.
- MolDock Score was used to evaluate the interaction energy of the indolin-2-one derivatives with FLT3.
Main Results:
- The predictive model demonstrated reasonable binding conformations of ligands with FLT3, validating its use for predicting interaction energies.
- Compound 1 exhibited the most stable interaction energy (-233.25 kcal mol⁻¹) among the studied inhibitors, significantly outperforming Sunitinib (-160.94 kcal mol⁻¹).
- Compounds IAF70, IAF72, IAF75, IAF80, IAF84, and IAF88 were identified as promising FLT3 inhibitors, while IAF79 showed potential as a dual Aurora B/FLT3 inhibitor.
Conclusions:
- The study successfully identified several indolin-2-one derivatives with significant potential for FLT3 inhibition and anticancer activity, particularly against AML.
- Compound 1 and the identified promising derivatives warrant further synthesis and biological evaluation.
- The molecular pattern of IAF79 suggests its utility in developing new indolin-2-one-based drugs targeting both FLT3 and Aurora B for broader cancer treatment.
