In silico models of drug transport to enhance personalized medicine – IMOTEP

The IMOTEP (In silico MOdels of drug Transport to Enhance Personalized medicine) research project aims at building in silico molecular models of key pharmacological events of the patient response to multidrug treatments. A series of six human membrane transporters (solute carrier - SLC - and ATP-binding cassette - ABC transporters), namely OAT1/3, OATP1B1/1B3 and MRP2/4, will be constructed in silico by homology modeling techniques and molecular dynamics (MD) simulations to elucidate key structural features. Drug-transporter interactions will be studied by (static and dynamic) docking procedures, followed by MD simulations to explore the surrounding of the binding sites. The specificity (if any) of the substrate-transporter interaction will provide insights at the atomistic level, which will improve a knowledge which is currently highly fragmented. A series of prototypical substrate-drugs or drugs including those used in organ transplantation, as a representative clinical situation requiring multidrug treatments (e.g., cyclosporin, mycophenolic acid, nucleic acid-like antivirals, penicillin) will be docked in the six transporters. Special attention will be paid to drug-drug interactions (DDI) involving membrane transporters. Genetic variants will also be constructed to mimic frequent or rare single nucleotide polymorphisms (SNPs) or other mutations in the genes coding these membrane transporters and identified in patient samples stored in biological collections. The impact of point mutation on the protein structure will be predicted in silico and translated in terms of function of the drug transporter.
The predictive capacity of the in silico models will be supported by in vitro experiments made on biomimetic models (mainly tethered lipid bilayer membranes - tBLMs), which will allow functional embedding of the different transporters and evaluation of drug transport. As a further step, the results observed in silico and in biomimetic models will be compared to in vitro experiments made with cell lines overexpressing the different transporters, namely HEK293T cells transitorily transfected with plasmids containing WT or variant (mutant obtained by site-directed mutagenesis) transporter genes.
IMOTEP will be carried out by using a multidisciplinary expertise involving the young research host unit (INSERM U1248) but also biophysicists from Technology university of Compiègne partner (CNRS U7025) and theoretical chemists from Palacky University of Olomouc (RCPTM). The complementary expertise of the different partners will allow for a multiscale approach: from atoms to clinical situation. The linkages from atoms to patients (atom ? macromolecule ? cell ? organ ? patient) will be performed thanks to a dual approach. IMOTEP will be initiated by a top-down approach, in which well-defined clinical data about, e.g., DDIs and genetic variants will guide the creation of the in silico models. Once models are validated, they will be used in a bottom-up approach to enable simulating inter-individual variability of the pharmacological response as well as to understand and predict observed or suspected clinically relevant DDI mediated by membrane transporters.
IMOTEP offers a unique opportunity to gather a consortium encompassing such a multiscale strategy dedicated to personalized medicine for organ transplant recipients. Organ transplantation is indeed a prototypical example for transporter-related DDI exploration, for which the young researcher’s unit has a long-lasting expertise in the related pharmacology, with an actual impact on clinical decisions. However, these models will be transferable to any pathology requiring multidrug treatments and/or in which similar membrane transporters are involved (e.g., chemotherapy, drug crossing the blood-brain barrier).