Development of an In Silico Prediction Model for P-glycoprotein Efflux Potential in Brain Capillary Endothelial Cells toward the Prediction of Brain Penetration

Abstract

Developing in silico models to predict the brain penetration of drugs remains a challenge owing to the intricate involvement of multiple transport systems in the blood brain barrier, and the necessity to consider a combination of multiple pharmacokinetic parameters. P-glycoprotein (P-gp) is one of the most important transporters affecting the brain penetration of drugs. Here, we developed an in silico prediction model for P-gp efflux potential in brain capillary endothelial cells (BCEC). Using the representative values of P-gp net efflux ratio in BCEC, we proposed a novel prediction system for brain-to-plasma concentration ratio (K p,brain ) and unbound brain-to-plasma concentration ratio (K p,uu,brain ) of P-gp substrates. We validated the proposed prediction system using newly acquired experimental brain penetration data of 28 P-gp substrates. Our system improved the predictive accuracy of brain penetration of drugs using only chemical structure information compared with that of previous studies.

Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders

“…While both in vitro and in vivo assays are used in drug discovery, there is often a lack of correlation between the two, likely due to differential expression of P-gp in different cell lines. Therefore, it is preferable to calculate these PK parameters using in vivo experiments in rodents-despite the inherent limitation that differences in P-gp expression or in transport potentials of substrates across species likely exist [104] Furthermore, MK-7622 was shown to reverse scopolamine's effects at 3 mg/kg in a mouse contextual fear conditioning assay [100]. Merck began a Phase 2 trial in 2013 to evaluate the compound's tolerability and efficacy as a symptomatic adjunct to donepezil therapy.…”

“…While both in vitro and in vivo assays are used in drug discovery, there is often a lack of correlation between the two, likely due to differential expression of P-gp in different cell lines. Therefore, it is preferable to calculate these PK parameters using in vivo experiments in rodents—despite the inherent limitation that differences in P-gp expression or in transport potentials of substrates across species likely exist [ 104 ]…”

The Application of in silico Methods for Prediction of Blood-Brain Barrier Permeability of Small Molecule PET Tracers

“…The most abundant efflux transporters in the human BBB are P-gp and BCRP (14,15). For the former, several in silico models have been reported for classifying if a compound is a P-gp substrate or not (75)(76)(77)(78). However, none of them show excellent accuracy.…”

In Silico Approaches for Addressing Challenges in CNS Radiopharmaceutical Design

“… − Each step in the radiopharmaceutical development process presents unique, nontrivial challenges: lead compound identification is typically followed by multistep synthesis and characterization of both the nonradioactive reference standard and one or more radiosynthetic precursors. Although currently available tools such as in vitro assays and high-throughput screening (HTS) methods are useful in the preliminary design of candidate molecules and derisking candidates early on by screening individual aspects of in vivo success (e.g., affinity, metabolism, , PgP-efflux, − etc. ), comprehensive evaluation of novel tracer candidates ultimately requires radiolabeling and preclinical in vivo imaging studies. − To that end, suitable radiosynthetic methods must be developed and applied to radiolabeling the precursor molecule, often requiring prolonged screening and optimization of reaction conditions to yield specialized automated synthetic methods for reproducibly producing high-quality radiopharmaceuticals.…”