A Novel Approach for Predicting P-Glycoprotein (ABCB1) Inhibition Using Molecular Interaction Fields

Abstract

P-glycoprotein (Pgp or ABCB1) is an ABC transporter protein involved in intestinal absorption, drug metabolism and brain penetration, and its inhibition can seriously alter a drug's bioavailability and safety. In addition, inhibitors of Pgp can be used to overcome multidrug resistance. Given this dual-purpose, reliable in silico procedures to predict Pgp inhibition are of great interest. A large and accurate literature collection yielded more than 1200 structures; a model was then constructed using various MIF-based technologies, considering pharmacophoric features and those physico-chemical properties related to membrane partitioning. High accuracy was demonstrated internally, with two different validation sets, and moreover using a number of molecules, for which Pgp inhibition was not experimentally available but was evaluated `inhouse'. All the validations confirmed the robustness of the model and its suitability to help medicinal chemists in drug discovery. The information derived from the model was rationalized as a pharmacophore for competitive Pgp inhibition.

Genomic and transcriptomic profiling of resistant CEM/ADR-5000 and sensitive CCRF-CEM leukaemia cells for unravelling the full complexity of multi-factorial multidrug resistance

“…“cell death of leukaemia cell lines”, “apoptosis” and “transport of cyclosporine”. Cyclosporine represents a well-known inhibitor of P-glycoprotein/ ABCB1 4647 and up-regulated P-glycoprotein/ABCB1 expression leads to increased cyclosporine efflux48. ABCB1 influenced a number of other biological functions and pathways, and PXR/RXR activation was among these pathways.…”

Ligand Promiscuity between the Efflux Pumps Human P-Glycoprotein and S. aureus NorA

“…Interestingly, medium-size compounds are able to inhibit only NorA. (3) A previous analysis 18 concluded that at least one polar feature (HB accepting group) is necessary for binding with Pgp. Here we confirm this hypothesis for both the proteins.…”

Substrate recognition by P-glycoprotein efflux transporters: Structure-ATPase activity relationship of diverse chemicals and agrochemicals

“…In addition, from the point of view of early absorption, distribution, metabolism, and excretion (ADME) prediction of therapeutic agents, various computational prediction models have been reported for ligand interactions with P-gp. 2,[4][5][6][7][8][9][10] In general, a P-gp substrate seems to be lipophilic or amphiphilic, having a large size or molecular volume, electronegative groups and hydrogen bonding groups. 11) Although X-ray structures of the complex of mouse P-gp with enantiomeric cyclic peptide inhibitors have been reported previously by Aller et al in 2009, 12) the mechanism of P-gp substrate/inhibitor recognition is complicated and still poorly understood.…”