In Silico Evaluation of Metabolites from the Philippine Invasive Plants Eichhornia crassipes and Imperata cylindrica Against BCR-ABL, P-glycoprotein, and Bcl-2 in the Context of Multidrug-Resistant K562 Chronic Myeloid Leukemia

Multidrug resistance (MDR) limits tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML) and arises through mutation of BCR-ABL, efflux by P-glycoprotein (P-gp), and survival signaling through Bcl-2. Flavonoids and terpenoids from plants are reported to act on efflux and apoptosis, and two invasive Philippine plants, Eichhornia crassipes (water hyacinth) and Imperata cylindrica (cogon grass), provide abundant biomass that contains compounds of both kinds. To our knowledge, their metabolites have not been evaluated against the three resistance mechanisms together. Ten metabolites, one of them an ascidian alkaloid comparator, were docked with AutoDock Vina 1.2 into the wild-type and T315I ABL1 kinase, two P-gp structures, and Bcl-2, with imatinib, verapamil, and venetoclax as controls and palmitic acid, cholesterol, and squalene as baseline compounds. Redocking reproduced the crystal pose for Bcl-2 (RMSD 0.57 Å) and wild-type ABL1 (0.43 Å), reproduced the T315I pose in one of three seeds, and did not reproduce the taxol pose in P-gp (RMSD above 6 Å), so the P-gp results are exploratory. No metabolite approached imatinib (gap 3.0 kcal/mol in wild-type ABL1) or venetoclax (gap 2.3 kcal/mol). The control drugs made 17 to 20 residue contacts with three to seven polar contacts, whereas the triterpenoids and sterols made 8 to 14 residue contacts with at most two polar contacts, and squalene, a hydrocarbon, matched imatinib in the T315I kinase (−9.68 against −9.46 kcal/mol). Eight of ten metabolites outscored verapamil in P-gp structure 6QEX, and so did squalene and cholesterol, which indicates that the hydrophobic cavity rewards lipophilic molecules in general. In ABL1, rhoifolin and the triterpenoids made no contact with the hinge residue Met318. Sequential docking with a fixed primary ligand gave positive changes in score in three of four pairs, which reflects competition for space. Fernenol and arundoin exceeded the baseline compounds in Bcl-2 by about 1 kcal/mol, and rhoifolin ranked among the top four metabolites in all five structures, so these three are the candidates prioritized for experimental testing.