Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity

Ítalo Antônio Fernandes; Déborah Braga Resende; Teodorico Castro Ramalho; Kamil Kuca; Elaine Fontes Ferreira da Cunha

doi:10.3390/molecules25071726

Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity

Molecules. 2020 Apr 9;25(7):1726. doi: 10.3390/molecules25071726.

Authors

Ítalo Antônio Fernandes¹, Déborah Braga Resende², Teodorico Castro Ramalho^{1

3}, Kamil Kuca³, Elaine Fontes Ferreira da Cunha¹

Affiliations

¹ Department of Chemistry, Federal University of Lavras, P.O. Box 3037, Lavras-MG 37200-000, Brazil.
² Department of Veterinary Medicine, Federal University of Lavras, P.O. Box 3037, Lavras-MG 37200-000, Brazil.
³ Faculty of Science, Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.

Abstract

FLT3 and dual Aurora B/FLT3 inhibitors have shown relevance in the search for promising new anticancer compounds, mainly for acute myeloid leukemia (AML). This study was designed to investigate the interactions between human FLT3 in the kinase domain with several indolin-2-one derivatives, structurally similar to Sunitinib. Molegro Virtual Docker (MVD) software was utilized in docking analyses. The predicted model of the training group, considering nineteen amino acid residues, performed in Chemoface, achieved an R² of 0.82, suggesting that the binding conformations of the ligands with FLT3 are reasonable, and the data can be used to predict the interaction energy of other FLT3 inhibitors with similar molecular patterns. The MolDock Score for energy for compound 1 showed more stable interaction energy (-233.25 kcal mol^-1) than the other inhibitors studied, while Sunitinib presented as one of the least stable (-160.94 kcal mol^-1). Compounds IAF70, IAF72, IAF75, IAF80, IAF84, and IAF88 can be highlighted as promising derivatives for synthesis and biological evaluation against FLT3. Furthermore, IAF79 can be considered to be a promising dual Aurora B/FLT3 inhibitor, and its molecular pattern can be exploited synthetically to search for new indolin-2-one derivatives that may become drugs used in the treatment of cancers, including AML.

Keywords: computational chemistry; dual Aurora B/FLT3 inhibitors; indolin−2-one derivatives.

MeSH terms

Algorithms
Aurora Kinase B / antagonists & inhibitors*
Aurora Kinase B / chemistry
Enzyme Activation / drug effects
Humans
Inhibitory Concentration 50
Models, Molecular
Models, Theoretical*
Molecular Conformation
Molecular Structure
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / chemistry

Substances

Protein Kinase Inhibitors
FLT3 protein, human
fms-Like Tyrosine Kinase 3
AURKB protein, human
Aurora Kinase B

Abstract

MeSH terms

Substances

Grants and funding