Periodic Reporting for period 1 - HumBrain (Computational modelling of the human brain lipidome)
Período documentado: 2022-03-01 hasta 2024-02-29
The HumBrain project addresses the problem of how to improve blood-brain barrier (BBB) penetration of therapeutics for the treatment of central nervous system (CNS) disorders using molecular modelling techniques. In addition, the project probes the role of of a protein in the BBB, the P-glycoprotein efflux pump, which is associated with multidrug resistance to chemotherapeutics in treating glioblastoma, a particularly deadly form of cancer with an extremely low survival rate.
The societal importance of the HumBrain project arise from the fact that the number of people living with neurodegenerative disorders are set to double by 2050, with Alzheimer’s disease in particular set to become a public health emergency. Similarly, it is currently very difficult to treat brain cancers, including glioblastomas, in part due to the challenge in achieving significant brain distribution of chemotherapeutics at the tumour site. With this MSC Action we turn to precision medicine with molecular modelling to improve the understanding of the role of the blood-brain barrier in limiting the delivery of therapeutics, as well as how pumps can be regulated to improve the delivery and availability fraction of a chemotherapeutic agent.
The overall objectives to HumBrain are: (1) to elucidate P-gp protein modulation by ligands to stop multidrug resistance, as the project sets out to map the P-gp binding site for the substrate rhodamine-123 by MD simulations, and compare this to the mechanism of binding for a promising third generation P-gp efflux inhibitor, tariquidar; (2) to elucidate the P-gp protein dynamics when embedded in a complex membrane at the atomistic and coarse grain levels; and (3) to elucidate CNS penetration mechanism across the blood-brain barrier by calculating the free-energy of partitioning of substrate molecule across the BBB, as well as calculate the interaction of tariquidar with P-gp in the binding site.
The conclusion of HumBrain are that we found novel insights into the mechanism by which tariquidar inhibits P-gp, which is crucial to dealing with the problem of multidrug resistance to chemotherapeutics. The MSC Action has thus contributed novel insights to designing methods to improve the delivery of chemotherapeutics to brain cancer patients. We uncovered novel mechanistic insights into how drugs cross the blood-brain barrier using precision medicine computational models.
The societal importance of the HumBrain project arise from the fact that the number of people living with neurodegenerative disorders are set to double by 2050, with Alzheimer’s disease in particular set to become a public health emergency. Similarly, it is currently very difficult to treat brain cancers, including glioblastomas, in part due to the challenge in achieving significant brain distribution of chemotherapeutics at the tumour site. With this MSC Action we turn to precision medicine with molecular modelling to improve the understanding of the role of the blood-brain barrier in limiting the delivery of therapeutics, as well as how pumps can be regulated to improve the delivery and availability fraction of a chemotherapeutic agent.
The overall objectives to HumBrain are: (1) to elucidate P-gp protein modulation by ligands to stop multidrug resistance, as the project sets out to map the P-gp binding site for the substrate rhodamine-123 by MD simulations, and compare this to the mechanism of binding for a promising third generation P-gp efflux inhibitor, tariquidar; (2) to elucidate the P-gp protein dynamics when embedded in a complex membrane at the atomistic and coarse grain levels; and (3) to elucidate CNS penetration mechanism across the blood-brain barrier by calculating the free-energy of partitioning of substrate molecule across the BBB, as well as calculate the interaction of tariquidar with P-gp in the binding site.
The conclusion of HumBrain are that we found novel insights into the mechanism by which tariquidar inhibits P-gp, which is crucial to dealing with the problem of multidrug resistance to chemotherapeutics. The MSC Action has thus contributed novel insights to designing methods to improve the delivery of chemotherapeutics to brain cancer patients. We uncovered novel mechanistic insights into how drugs cross the blood-brain barrier using precision medicine computational models.
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.
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.
HumBrain has pushed the frontiers of our understanding of the blood-brain barrier and the role of the P-gp protein in multidrug resistance to chemotherapeutics. The published work on modelling the substrate entry into P-gp is a first of its kind for P-gp, and elucidates the way in which P-gp operates at the atomic level, which opens up novel strategies for modulating P-gp, and thereby advancing the fight against multidrug resistance.
The Fellow exceeded goals by leading a forthcoming perspective on the blood-brain barrier, which utilises his experience acquired during the MSCA fellowship. The MSCA allowed the Fellow to present at major health institutes in the United States, in particular the US National Institutes of Health and the US Food and Drug Administration. The MSCA gave the Fellow the necessary exposure to seek admission and continue work with steering committees of large scientific organizations (Biophysical Society) and the boards of tier-one journals (JCIM).
HumBrain has wider societal impacts, including the discovery of new insights into how the blood-brain barrier functions and its relationship with P-gp. The dissemination of our findings in tier-one journals ensures the relevant specialist audience can access these findings and continue to target P-gp in clinical trials with the new findings we have on P-gp inhibition with tariquidar. A final overarching impact is the increased focus on the public health emergency that is neurodegerative disorders and multidrug resistance to chemotherapeutics.
The Fellow exceeded goals by leading a forthcoming perspective on the blood-brain barrier, which utilises his experience acquired during the MSCA fellowship. The MSCA allowed the Fellow to present at major health institutes in the United States, in particular the US National Institutes of Health and the US Food and Drug Administration. The MSCA gave the Fellow the necessary exposure to seek admission and continue work with steering committees of large scientific organizations (Biophysical Society) and the boards of tier-one journals (JCIM).
HumBrain has wider societal impacts, including the discovery of new insights into how the blood-brain barrier functions and its relationship with P-gp. The dissemination of our findings in tier-one journals ensures the relevant specialist audience can access these findings and continue to target P-gp in clinical trials with the new findings we have on P-gp inhibition with tariquidar. A final overarching impact is the increased focus on the public health emergency that is neurodegerative disorders and multidrug resistance to chemotherapeutics.