HumBrain was conducted via 5 work packages. We built a simulation model of P-glycoprotein in a membrane model of the human BBB to investigate the interaction of substrates and inhibitors with P-glycoprotein. This work resulted in a tier-one journal publication, and a presentation at a major international conference, as well as a conference manuscript. Then we built a novel coarse-grained model of P-gp, and for which a manuscript is under preparation. We calculated free-energy calculations along the blood-brain barrier and in the P-gp model, which resulted in a tier-one journal publication. Finally, we disseminated our work in multiple international scientific meetings, as well as via many invited talks at foreign universities. The Fellow delivered keynote/oral presentations at two major scientific conferences in Europe, had multiple invited talks at major research institutions in the US and Europe, as well as multiple poster presentations at major conferences.
The main results of HumBrain are: (1) novel insights into how drugs interact with the blood-brain barrier membrane, with our published data in the Journal of Medicinal Chemistry suggesting that the inhibitor tariquidar works in a manner that was so-far unknown, namely by aggregating prior to binding, which can help to further the work on P-gp inhibition to tackle multidrug resistance to chemotherapeutics; (2) a novel coarse-grain model of the blood-brain barrier, which can serve to screen for BBB crossing at a much faster rate; and (3) a novel method to rapidly screen compound permeability across the blood-brain barrier.
HumBrain results were disseminated in: (1) a journal publication in J. Med. Chem. elucidating the mechanism of entry for a common chemotherapeutic to P-gp, including the first mechanistic study of action of a potent third generation P-gp inhibitor; (2) a forthcoming paper on a coarse-grained model of P-gp, and how this can be used to glean new insights into the origin of multidrug resistance by accessing much longer simulation timescales; (3) a journal publication in J. Comp. Aided Drug Design on how to calculate blood-brain barrier permeabilities using simulations to rank compounds rapidly, with an approach that enables users with few computational resources to test whether new therapeutics can cross the BBB; and (4) a forthcoming perspective on how to combine simulation and experimental methodologies for arriving at complex membrane permeabilities.
Project result exploitation: The code and resulting simulation structures from this work are disseminated for immediate utilisation via the HumBrain MSCA project website.
