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. 2023 Mar 1;28(5):2289.
doi: 10.3390/molecules28052289.

Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin's Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles

Abdalrahim M Ali  1 , Alaa A Makki  1 , Walaa Ibraheem  1 , Mohammed Abdelrahman  2 , Wadah Osman  3   4 , Asmaa E Sherif  3   5 , Ahmed Ashour  3   5 , Sabrin R M Ibrahim  6   7 , Kholoud F Ghazawi  8 , Waad A Samman  9 , Abdulrahim A Alzain  1
Affiliations

Design of Novel Phosphatidylinositol 3-Kinase Inhibitors for Non-Hodgkin's Lymphoma: Molecular Docking, Molecular Dynamics, and Density Functional Theory Studies on Gold Nanoparticles

Abdalrahim M Ali et al. Molecules. .

Abstract

Non-Hodgkin's lymphomas are a diverse collection of lymphoproliferative cancers that are much less predictable than Hodgkin's lymphomas with a far greater tendency to metastasize to extranodal sites. A quarter of non-Hodgkin's lymphoma cases develop at extranodal sites and the majority of them involve nodal and extranodal sites. The most common subtypes include follicular lymphoma, chronic/small lymphocytic leukaemia, mantel cell lymphoma, and marginal zone lymphoma. Umbralisib is one of the latest PI3Kδ inhibitors in clinical trials for several hematologic cancer indications. In this study, new umbralisib analogues were designed and docked to the active site of PI3Kδ, the main target of the phosphoinositol-3-kinase/Akt/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR). This study resulted in eleven candidates, with strong binding to PI3Kδ with a docking score between -7.66 and -8.42 Kcal/mol. The docking analysis of ligand-receptor interactions between umbralisib analogues bound to PI3K showed that their interactions were mainly controlled by hydrophobic interactions and, to a lesser extent, by hydrogen bonding. In addition, the MM-GBSA binding free energy was calculated. Analogue 306 showed the highest free energy of binding with -52.22 Kcal/mol. To identify the structural changes and the complexes' stability of proposed ligands, molecular dynamic simulation was used. Based on this research finding, the best-designed analogue, analogue 306, formed a stable ligand-protein complex. In addition, pharmacokinetics and toxicity analysis using the QikProp tool demonstrated that analogue 306 had good absorption, distribution, metabolism, and excretion properties. Additionally, it has a promising predicted profile in immune toxicity, carcinogenicity, and cytotoxicity. In addition, analogue 306 had stable interactions with gold nanoparticles that have been studied using density functional theory calculations. The best interaction with gold was observed at the oxygen atom number 5 with -29.42 Kcal/mol. Further in vitro and in vivo investigations are recommended to be carried out to verify the anticancer activity of this analogue.

Keywords: cancer; drug discovery; gold nanoparticles; health and wellbeing; molecular docking; molecular dynamics; pi3k; umbralisib analogues.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
2D interaction of umbralisib in the active site of PI3Kδ protein (PDB ID:4XE0) using the QPLD tool of Maestro software. The hydrogen bond interactions with residues are represented by a purple dashed arrow directed towards the electron donor. The π-π interactions are represented by a green line.
Figure 2
Figure 2
Potential interaction sites of umbralisib in the active site of PI3Kδ using the Ligand Designer tool of Maestro software. Potential hydrogen bond donor sites are indicated by green cones. While potential hydrogen bond acceptor interaction sites are indicated by red hemispheres. Potential hydrophobic interaction sites are indicated by yellow spheres and rings, respectively.
Figure 3
Figure 3
Chemical structures of the eleven analogues that showed promising binding affinity against PI3Kδ protein (PDB ID: 4XE0) using the Ligand Designer tool of Maestro software.
Figure 4
Figure 4
2D interaction of the top three analogues and the reference in complex with PI3Kδ protein (PDB ID:4XE0) using the XP docking mode of Glide software. The hydrogen bond interactions with residues are represented by a purple dashed arrow directed towards the electron donor. The hydrophobic residues are in green colour. (A) Analogue 188, (B) analogue 202, (C) analogue 306, and (D) umbralisib.
Figure 5
Figure 5
Binding poses of (A) Analogue 306 PI3Kδ complex. (B) Analogue 202 PI3Kδ complex. (C) Analogue 188 PI3Kδ complex. (D) Umbralisib PI3Kδ complex. Ligands are shown in the stick models. PI3Kδ is shown in the ribbon model (blue dashed lines represent hydrophobic bonds, whereas yellow lines represent hydrogen bonds).
Figure 6
Figure 6
(A) Structure of umbralisib. (B) The substitution pattern observed in the best-designed analogues.
Figure 7
Figure 7
The protein–ligand RMSD plot of the top compound and the reference complexed with PI3Kδ protein (PDB ID:4XE0) during 100 ns molecular dynamics simulation using Desmond software. (A) Analogue 306 and (B) umbralisib.
Figure 8
Figure 8
The RMSF plot of the PI3Kδ protein (PDB ID:4XE0) complexed the top compound and the reference during 100 ns molecular dynamics simulation using Desmond software. (A) Analogue 306 and (B) umbralisib.
Figure 9
Figure 9
The protein–ligand contact histogram of the top compound and the reference complexed with PI3Kδ protein (PDB ID:4XE0) during 100 ns molecular dynamics simulation using Desmond software. (A) Analogue 306 and (B) umbralisib.
Figure 10
Figure 10
(A) Initial and (B) optimised geometry for the analogue 306 (oxygen atom number five) interaction with the gold atoms using Gaussian software.
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