Discovering Anti-platelet Drug Combinations with an Integrated Model
of Activator-Inhibitor Relationships,Activator-Activator Synergies and
Inhibitor-Inhibitor Synergies |
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Authors: | Federica Lombardi Kalyan Golla Darren J Fitzpatrick Fergal P Casey Niamh Moran Denis C Shields |
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Institution: | 1. Complex and Adaptive Systems Laboratory, University College Dublin,
Dublin, Ireland.; 2. Molecular and Cellular Therapeutics, Royal College of Surgeons in
Ireland, Dublin, Ireland.; 3. Conway Institute of Biomolecular and Biomedical Research, University
College Dublin, Dublin, Ireland.; 4. School of Medicine and Medical Sciences, University College Dublin,
Dublin, Ireland.; Tufts University, UNITED STATES, |
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Abstract: | Identifying effective therapeutic drug combinations that modulate complex
signaling pathways in platelets is central to the advancement of effective
anti-thrombotic therapies. However, there is no systems model of the platelet
that predicts responses to different inhibitor combinations. We developed an
approach which goes beyond current inhibitor-inhibitor combination screening to
efficiently consider other signaling aspects that may give insights into the
behaviour of the platelet as a system. We investigated combinations of platelet
inhibitors and activators. We evaluated three distinct strands of information,
namely: activator-inhibitor combination screens (testing a panel of inhibitors
against a panel of activators); inhibitor-inhibitor synergy screens; and
activator-activator synergy screens. We demonstrated how these analyses may be
efficiently performed, both experimentally and computationally, to identify
particular combinations of most interest. Robust tests of activator-activator
synergy and of inhibitor-inhibitor synergy required combinations to show
significant excesses over the double doses of each component. Modeling
identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and
complementarity between inhibitor-inhibitor synergy effects and
activator-inhibitor combination effects. This approach accelerates the mapping
of combination effects of compounds to develop combinations that may be
therapeutically beneficial. We integrated the three information sources into a
unified model that predicted the benefits of a triple drug combination targeting
ADP, thromboxane and thrombin signaling. |
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