biostudies-literatureJorgensen CEuropean Commission9050https://www.ebi.ac.uk/biostudies/studies/S-EPMC12469845biostudies-literatureUnknown26(18)We explored the pharmacology of the P-glycoprotein (P-gp) efflux pump and its role in multidrug resistance. We used Protein Data Bank (PDB) database mining and the artificial intelligence (AI) model Boltz-2.1.1, developed for simultaneous structure and affinity prediction, to explore the multimeric nature of recent P-gp inhibitors. We construct a MARTINI coarse-grained (CG) force field description of P-gp embedded in a model of the endothelial blood-brain barrier. We found that recent P-gp inhibitors have been captured in either monomeric, dimeric, or trimeric states. Our CG model demonstrates the ability of P-gp substrates to permeate and transition across the BBB bilayer. We report a multimodal binding model of P-gp inhibition in which later generations of inhibitors are found in dimeric and trimeric states. We report analyses of P-gp substrates that point to an extended binding surface that explains how P-gp can bind over 300 substrates non-selectively. Our coarse-grained model of substrate permeation into membranes expressing P-gp shows benchmarking similarities to prior atomistic models and provide new insights on far longer timescales.International journal of molecular sciencesSimulation and Machine Learning Assessment of P-Glycoprotein Pharmacology in the Blood-Brain Barrier: Inhibition and Substrate Transport.PMC12469845101023783Thulasi SLopez Martinez EPrior HDraheim RRBarker MGregory CJorgensen COliphant EFraney BWAjay AOluwasegun JfalseSimulation and Machine Learning Assessment of P-Glycoprotein Pharmacology in the Blood-Brain Barrier: Inhibition and Substrate Transport.We explored the pharmacology of the P-glycoprotein (P-gp) efflux pump and its role in multidrug resistance. We used Protein Data Bank (PDB) database mining and the artificial intelligence (AI) model Boltz-2.1.1, developed for simultaneous structure and affinity prediction, to explore the multimeric nature of recent P-gp inhibitors. We construct a MARTINI coarse-grained (CG) force field description of P-gp embedded in a model of the endothelial blood-brain barrier. We found that recent P-gp inhibitors have been captured in either monomeric, dimeric, or trimeric states. Our CG model demonstrates the ability of P-gp substrates to permeate and transition across the BBB bilayer. We report a multimodal binding model of P-gp inhibition in which later generations of inhibitors are found in dimeric and trimeric states. We report analyses of P-gp substrates that point to an extended binding surface that explains how P-gp can bind over 300 substrates non-selectively. Our coarse-grained model of substrate permeation into membranes expressing P-gp shows benchmarking similarities to prior atomistic models and provide new insights on far longer timescales.2025-01-01T00:00:00Z2025 Sep2026-05-02T03:17:11.962Z2026-05-02T03:11:42.894ZS-EPMC124698454100961510.3390/ijms26189050