SuperNatural inhibitors to reverse multidrug resistance emerged by ABCB1 transporter: Database mining, lipid-mediated molecular dynamics, and pharmacokinetics study

by Mahmoud A. A. Ibrahim, Khlood A. A. Abdeljawaad, Alaa H. M. Abdelrahman, Mahmoud M. H. Abdelhamid, Mohamed Ahmed Naeem, Gamal A. H. Mekhemer, Peter A. Sidhom, Shaban R. M. Sayed, Paul W. Paré, Mohamed-Elamir F. Hegazy

An effective approach to reverse multidrug resistance (MDR) is P-glycoprotein (P-gp, ABCB1) transport inhibition. To identify such molecular regulators, the SuperNatural II database, which comprises > 326,000 compounds, was virtually screened for ABCB1 transporter inhibitors. The Lipinski rule was utilized to initially screen the SuperNatural II database, identifying 128,126 compounds. Those natural compounds were docked against the ABCB1 transporter, and those with docking scores less than zosuquidar (ZQU) inhibitor were subjected to molecular dynamics (MD) simulations. Based on MM-GBA binding energy (ΔG_binding) estimations, UMHSN00009999 and UMHSN00097206 demonstrated ΔG_binding values of –68.3 and –64.1 kcal/mol, respectively, compared to ZQU with a ΔG_binding value of –49.8 kcal/mol. For an investigation of stability, structural and energetic analyses for UMHSN00009999- and UMHSN00097206-ABCB1 complexes were performed and proved the high steadiness of these complexes throughout 100 ns MD simulations. Pharmacokinetic properties of the identified compounds were also predicted. To mimic the physiological conditions, MD simulations in POPC membrane surroundings were applied to the UMHSN00009999- and UMHSN00097206-ABCB1 complexes. These results demonstrated that UMHSN00009999 and UMHSN00097206 are promising ABCB1 inhibitors for reversing MDR in cancer and warrant additional in-vitro/in-vivo studies.