Predicting in silico which mixtures of the natural products of plants might most effectively kill human leukemia cells?

Abstract

The aim of the analysis of just 13 natural products of plants was to predict the most likely effective artificial mixtures of 2-3 most effective natural products on leukemia cells from over 364 possible mixtures. The natural product selected included resveratrol, honokiol, chrysin, limonene, cholecalciferol, cerulenin, aloe emodin, and salicin and had over 600 potential protein targets. Target profiling used the Ontomine set of tools for literature searches of potential binding proteins, binding constant predictions, binding site predictions, and pathway network pattern analysis. The analyses indicated that 6 of the 13 natural products predicted binding proteins which were important targets for established cancer treatments. Improvements in effectiveness were predicted for artificial combinations of 2 or 3 natural products. That effect might be attributed to drug synergism rather than increased numbers of binding proteins bound (dose effects). Among natural products, the combinations of aloe emodin with mevinolin and honokiol were predicted to be the most effective combination for AML-related predicted binding proteins. Therefore, plant extracts may in future provide more effective medicines than the single purified natural products of modern medicine, in some cases.

Figure 1

Subnetwork dysregulated in AML versus normal white blood cells. Interaction-type annotations from KEGG were shown as the letters above the arrows where; E was enzymatic; T was transcription with subscript + showing activation and − showing inhibition; B was protein-to-protein binding. Subscripts for the predicted protein-to-protein interactions were c: for compound interactions, +: activation, −: inhibition, i: an indirect effect, s: a state change, p+: phosphorylation, p−: dephosphorylation, m: methylation, u: ubiquitination, g: glycosylation and “none” for missing information.

Figure 2

Aloe emodin was predicted to be bound at the centre surrounded by the amino acid residues from the active site of 2GDZ. It can be seen that aloe emodin forms 4 hydrogen bonded interactions with the residues of the active site. These hydrogen bonded interactions are partly responsible for stabilizing the ligand-protein complex. In addition the hydrophobic interactions present between the ligand and the protein are displayed as wireframe spheres.

Figure 3

Drug combination selections. Values inside beige squares were the Combiscores. Each black box was the mean used to derive the cutoff.