Chemosensitizing Glycolipids from Ipomoea murucoides: Affinity-Directed Fractionation Using G6Pase, In Vitro Evaluation in MDR Cells, and In Silico Analysis in P-gp

Abstract The multidrug resistance phenotype is a major cause of cancer chemotherapy failure. To identify novel chemosensitizing glycolipids capable of modulating resistance in vinblastine-resistant human breast cancer cells, a methanol-soluble extract from the flowers of Ipomoea murucoides Roem. & Schult., Convolvulaceae, commonly known as cazahuate in Nahuatl (Mexico), was used. The extract was fractionated through affinity-directed fractionation using liver glucose-6-phosphatase enzymes. Biological evaluation revealed that the affinity-directed fractions significantly enhanced vinblastine activity in resistant cells, achieving up to a 57-fold increase, compared to a 43-fold enhancement by reserpine (positive control). Additionally, molecular docking analyses were performed to determine the ligand-binding sites of selected murucoidins in P-glycoprotein (ABCB1). The selected glycolipids interacted with the transmembrane domains and the nucleotide-binding domain 2 (NBD2) site of P-glycoprotein, showing binding energies of − 3.65 and − 4.97 kcal/mol for murucoidin V, and − 6.85 and − 5.2 kcal/mol for murucoidin XIV, respectively. However, their stronger binding affinities and more extensive hydrogen bonding interactions with the transmembrane domains suggest that this region is their primary site of action. These findings suggest that I. murucoides glycolipids may overcome multidrug resistance by targeting P-glycoprotein, offering potential as chemosensitizing agents. Graphical Abstract