Computational and theoretical insights into the cytotoxic prospects of compounds isolated from Elaeodendron buchananii against Leukemia

Abstract

The present study investigated the cytotoxic prospects of isolated compounds from Elaeodendron buchananii against leukemia, using computational tools. Comprehensive literature searches revealed only buchaninoside, mutangin, methyl 3β-acetoxy-11α, 19α, 28-trihydroxyurs-12-en-23-oic acid, 3β, 11α, 19α-trihydroxyurs-12-en-23, 28-dioic acid, 3β-acetoxy-19α, 24, 28-trihydroxyurs-12-ene, 3-oxo-19α,28-dihydroxyurs-12-en-24-oic acid, and elabunin have been isolated from E. buchananii. The compounds were subjected to Density Functional Theory (DFT) and Molecular Dynamics (MD) analyses, with Fms-like tyrosine kinase (FLT3) and catalytic binding sites of Murine Leukemia Virus (MLV) as the target proteins in lukemia. Following DFT analysis, the structures of the compounds were optimized at the PW6B95D3/Def2-TZVP level of theory; their UV-Visible peaks were in the UV region, with mutangin, 3-oxo-19α,28-dihydroxyurs-12-en-24-oic acid and elabunin exhibiting one single peak. The potent Root-Mean-Square Deviation, Root-Mean-Square Fluctuation, solvent-accessible surface area and radius of gyration values indicated a strong and stable molecular interaction between the compounds and the proteins. These were further supported by high ∆G values, with MLV showing the best interaction. Per-residue decomposition plots also revealed high energy contributions in the interactions' binding sites residues. These results indicate that the cytotoxic prospects of the isolated compounds against leukemia as indicated by its molecular interactions with FLT3 and MLV.

Keywords: And Lukemia; Anticancer; Computation; Cytotoxicity; Elaeodendron buchananii.

Graphical abstract

Fig. 1

Isolated compounds from E. buchananii.

Fig. 2

Structures of the investigated compounds as optimized at the PW6B95D3/Def2-TZVP level of theory. Detailed names of the compounds are provided in the text.

Fig. 3

UV-Vis spectra of compounds 2, 4, 6 and 7 computed using TD-DFT at the PW6B95D3/Def2-TZVP level of theory.

Fig. 4

Infrared spectra of the studied compounds as calculated at the PW6B95D3/Def2-TZVP level of theory.

Fig. 5

Structural representation of alterations occurring during the binding of the seven compounds bound to FLT3. The (A) conformational stability, C-α atoms RMSD FLT3 to the compounds ran for 100 ns MD simulation. (B) The time evolution RMSF of each residue of the enzyme C-α atom over 100 ns for. (C) Solvent accessible surface area (SASA) backbone atoms relative to the starting minimized structure over 100 ns for FLT3. (D) C-α RoG plots and structural dynamics showing atomic distribution and compactness in various systems during 100 ns simulation period whereas the different colours represent each system atomic distribution structure conformation.

Fig. 6

Structural representation of alterations occurring during the binding of the compounds bound to MLV. The (A) conformational stability, C-α atoms RMSD MLV to the compounds ran for 100 ns MD simulation. (B) The time evolution RMSF of each residue of the enzyme C-α atom over 100 ns for. (C) Solvent accessible surface area (SASA) backbone atoms relative to the starting minimized structure over 100 ns for MLV. (D) C-α RoG plots and structural dynamics showing atomic distribution and compactness in various systems during 100 ns simulation period whereas the different colours represent each system atomic distribution structure conformation.

Fig. 7

Per-residue decomposition plots showing individual energy contributions to the binding and stabilization of the compounds at the binding sites of FLT3 (A) 3ß,11a,19a-trihydroxyurs (B) 3ß-acetoxy,28-trihydroxyurs (C) Buchaninoside (D) Elabunin (E) Methyl 3ß-acetoxy-11a (F) Mutangin (G) 3-Oxo9a,28-dihydroxyurs. This reveals that energy contributions were highest in binding sites residues.

Fig. 8

Per-residue decomposition plots showing individual energy contributions to the binding and stabilization of the compounds at the binding sites of MLV (A) 3ß,11a,19a-trihydroxyurs (B) 3ß-acetoxy,28-trihydroxyurs (C) Buchaninoside (D) Elabunin (E) Methyl 3ß-acetoxy-11a (F) Mutangin (G) 3-Oxo9a,28-dihydroxyurs. This reveals that energy contributions were highest in binding sites residues.