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. 2019 Dec 19;25(1):24.
doi: 10.3390/molecules25010024.

Modeling the Antileukemia Activity of Ellipticine-Related Compounds: QSAR and Molecular Docking Study

Edgar Márquez  1 , José R Mora  2 , Virginia Flores-Morales  3 , Daniel Insuasty  1 , Luis Calle  4
Affiliations

Modeling the Antileukemia Activity of Ellipticine-Related Compounds: QSAR and Molecular Docking Study

Edgar Márquez et al. Molecules. .

Abstract

The antileukemia cancer activity of organic compounds analogous to ellipticine representes a critical endpoint in the understanding of this dramatic disease. A molecular modeling simulation on a dataset of 23 compounds, all of which comply with Lipinski's rules and have a structure analogous to ellipticine, was performed using the quantitative structure activity relationship (QSAR) technique, followed by a detailed docking study on three different proteins significantly involved in this disease (PDB IDs: SYK, PI3K and BTK). As a result, a model with only four descriptors (HOMO, softness, AC1RABAMBID, and TS1KFABMID) was found to be robust enough for prediction of the antileukemia activity of the compounds studied in this work, with an R2 of 0.899 and Q2 of 0.730. A favorable interaction between the compounds and their target proteins was found in all cases; in particular, compounds 9 and 22 showed high activity and binding free energy values of around -10 kcal/mol. Theses compounds were evaluated in detail based on their molecular structure, and some modifications are suggested herein to enhance their biological activity. In particular, compounds 22_1, 22_2, 9_1, and 9_2 are indicated as possible new, potent ellipticine derivatives to be synthesized and biologically tested.

Keywords: QSAR; cancer; leukemia; molecular descriptors; molecular modeling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of ellipticine-analogous compounds studied in this work.
Figure 2
Figure 2
Experimental pIC50 vs. pIC50 predicted using Equation (3).
Figure 3
Figure 3
On the left, the 3D representation is shown, and on the right, the 2D interactions of compound 9 (a), fostamitinib (b), and compound 22 (c) at the active site of spleen tyrosine kinase (SYK).
Figure 3
Figure 3
On the left, the 3D representation is shown, and on the right, the 2D interactions of compound 9 (a), fostamitinib (b), and compound 22 (c) at the active site of spleen tyrosine kinase (SYK).
Figure 4
Figure 4
On the left, the 3D representation is shown, and on the right the 2D interactions of compounds 9 and 22 at the active site of PI3K.
Figure 5
Figure 5
Structures, pIC50, and scoring values against SYK protein for new proposed compounds based on QSAR results.
Figure 6
Figure 6
On the left, the 3D representation is shown, and on the right, the 2D interactions of the proposed compound at the spleen tyrosine kinase (SYK) active site.
Figure 7
Figure 7
Possible synthetic schema for proposed anticancer compounds. (1) Compounds 9_1 and 9_2. (2) Compounds 22_1 and 22_2.
See this image and copyright information in PMC

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