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. 2023 Apr 17;28(8):3531.
doi: 10.3390/molecules28083531.

Tuning the Biological Activity of PI3K δ Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow

Wojciech Pietruś  1   2 , Mariola Stypik  2   3 , Marcin Zagozda  2 , Martyna Banach  2 , Lidia Gurba-Bryśkiewicz  2 , Wioleta Maruszak  2 , Arkadiusz Leniak  2 , Rafał Kurczab  1 , Zbigniew Ochal  3 , Krzysztof Dubiel  2 , Maciej Wieczorek  2
Affiliations

Tuning the Biological Activity of PI3K δ Inhibitor by the Introduction of a Fluorine Atom Using the Computational Workflow

Wojciech Pietruś et al. Molecules. .

Abstract

As a member of the class I PI3K family, phosphoinositide 3-kinase δ (PI3Kδ) is an important signaling biomolecule that controls immune cell differentiation, proliferation, migration, and survival. It also represents a potential and promising therapeutic approach for the management of numerous inflammatory and autoimmune diseases. We designed and assessed the biological activity of new fluorinated analogues of CPL302415, taking into account the therapeutic potential of our selective PI3K inhibitor and fluorine introduction as one of the most frequently used modifications of a lead compound to further improve its biological activity. In this paper, we compare and evaluate the accuracy of our previously described and validated in silico workflow with that of the standard (rigid) molecular docking approach. The findings demonstrated that a properly fitted catalytic (binding) pocket for our chemical cores at the induced-fit docking (IFD) and molecular dynamics (MD) stages, along with QM-derived atomic charges, can be used for activity prediction to better distinguish between active and inactive molecules. Moreover, the standard approach seems to be insufficient to score the halogenated derivatives due to the fixed atomic charges, which do not consider the response and indictive effects caused by fluorine. The proposed computational workflow provides a computational tool for the rational design of novel halogenated drugs.

Keywords: CPL302415; MD; MM-GBSA; PI3Kδ; QPLD; asthma; fluorine; induced-fit docking; molecular docking.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of CPL302415.
Figure 2
Figure 2
Illustration of the binding mode of CPL302415 (2) in the catalytic center of PI3Kδ obtained by molecular docking [19].
Figure 3
Figure 3
Illustration of the binding modes of compounds 6 (green) and 10 (orange) in the catalytic center of PI3Kδ obtained by molecular docking.
Figure 4
Figure 4
Computational workflow used to predict the most potent fluorine derivative. The workflow began with the IFD of a nonfluorinated compound (core) (1) followed by 100 ns-long MD simulations (2), which were then clustered based on the RMSD matrix of the protein backbone (3). All derivatives were docked to the three most frequently observed conformations of the protein using the QPLD algorithm (4). Using the MM-GBSA approach, the binding energy (ΔG) was calculated for the three conformations of the ligand with the smallest RMSD of the core to nonfluorinated compounds (5). Finally, the difference in the interaction energy between the most active compound and subsequent isomers (ΔΔG) was calculated (6).
Figure 5
Figure 5
Superposition of the binding modes of core (A) tert-butyl piperazine (cyan), (B) benzylpiperazine (yellow), and (C) 4-benzylpiperazine-1-carbonyl (magenta) in the PI3Kδ catalytic sites. The selected complexes were the most populated conformations resulting from the clustering of the MD trajectories. The RMSD (Å) of compounds 2, 6, and 10, respectively, during MD simulations (D) indicates the stability of the ligand with respect to the protein and its binding pocket. Ligand RMSD is a measure of the internal fluctuations of ligand atoms.
Figure 6
Figure 6
Comparison of the binding mode coherence of core (A) tert-butyl piperazine, (B) benzylpiperazine, and (C) 4-benzylpiperazine-1-carbonyl obtained using the standard (rigid) molecular docking approach (I) and the proposed in silico workflow (II).
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References

    1. Foster J.G., Blunt M.D., Carter E., Ward S.G. Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies. Pharmacol. Rev. 2012;64:1027–1054. doi: 10.1124/pr.110.004051. - DOI - PubMed
    1. Banham-Hall E. The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases. Open Rheumatol. J. 2012;6:245–258. doi: 10.2174/1874312901206010245. - DOI - PMC - PubMed
    1. Stark A.-K., Sriskantharajah S., Hessel E.M., Okkenhaug K. PI3K inhibitors in inflammation, autoimmunity and cancer. Curr. Opin. Pharmacol. 2015;23:82–91. doi: 10.1016/j.coph.2015.05.017. - DOI - PMC - PubMed
    1. Puri K.D., Gold M.R. Selective inhibitors of phosphoinositide 3-kinase delta: Modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies. Front. Immunol. 2012;3:256. doi: 10.3389/fimmu.2012.00256. - DOI - PMC - PubMed
    1. Haselmayer P., Camps M., Muzerelle M., El Bawab S., Waltzinger C., Bruns L., Abla N., Polokoff M.A., Jond-Necand C., Gaudet M., et al. Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies. Front. Immunol. 2014;5:233. doi: 10.3389/fimmu.2014.00233. - DOI - PMC - PubMed