Abstract

2D AND 3D QSAR MODELING OF 2-AMINOPYRIMIDINE DERIVATIVES OR FLT3 KINASE INHIBITOR FOR THE TREATMENT OF ACUTE MYELOID LEUKAEMIA

*Debapriya Dey, Adarsha Ganguly, Snehasish Koner, Hirak Bhowmik, Debarghya Karforma, Sagar Dey, Subhas Chandra Hazari

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Abstract

Acute myeloid leukemia (AML) represents an aggressive hematological malignancy. In 2020, the American Cancer Society estimated 19,940 cases in the United States, with an estimated 11,180 deaths, emphasizing the urgent need for the development of novel and more effective therapeutic agents. In this work, thirty-two 2‑aminopyrimidine derivatives were collected from the recently published investigation. These compounds were reported to have activity against Fms-like tyrosine kinase 3 (FLT3) enzymes, which is considered as a promising target for the treatment of AML. More importantly, these compounds exhibited activity against both wild type and D835Y mutant enzymes. In this work, we performed ligand-based in silico approaches such as 2D-quantitative structure activity relationship (2D-QSAR) and 3D-QSAR to understand the structural requirements of these 2‑aminopyrimidine derivatives for higher biological activity against these enzyme targets. A range of feature selection techniques were employed for developing 2D-QSAR models and the best models were generated with highly satisfactory internal and external predictivity. More significantly, it was observed that limited number of descriptors with high interpretability are capable of developing models, the statistical qualities of which are similar to the models developed after including large number of 2D/3D complex descriptors. Therefore, the 2D-QSAR models presented in this work afford high statistical significance and mechanistic interpretation. The predictive validated 3D-QSAR models were developed with the structures aligned with unsupervised rigid body alignment method. These 3D-QSAR models revealed the importance of steric and electrostatic fields responsible for determining higher activity against these enzymes. Overall, the current work may be used as important guidelines to design novel FLT3 kinase inhibitors for the treatment of AML.

Keywords: 2D-QSAR, 3D-QSAR, 2-AMINOPYRIMIDINE DERIVATIVES, FLT3 KINASE INHIBITOR, ACUTE MYELOID LEUKAEMIA.