Gupta, M.; Feng, J.; Bhisetti, G. Experimental and Computational Methods to Assess Central Nervous System Penetration of Small Molecules. Molecules2024, 29, 1264.
Gupta, M.; Feng, J.; Bhisetti, G. Experimental and Computational Methods to Assess Central Nervous System Penetration of Small Molecules. Molecules 2024, 29, 1264.
Gupta, M.; Feng, J.; Bhisetti, G. Experimental and Computational Methods to Assess Central Nervous System Penetration of Small Molecules. Molecules2024, 29, 1264.
Gupta, M.; Feng, J.; Bhisetti, G. Experimental and Computational Methods to Assess Central Nervous System Penetration of Small Molecules. Molecules 2024, 29, 1264.
Abstract
In CNS drug discovery, estimation of brain exposure of lead compounds is critical for their optimization. Compounds need to cross the blood-brain barrier (BBB) to reach the pharmacological targets in the CNS. The BBB is a complex system involving passive and active mechanisms of transport and efflux transporters such as P-glycoproteins (P-gp) and breast cancer resistance protein (BCRP), which play an essential role in CNS penetration of small molecules. Several in vivo, in vitro and in silico methods are available to estimate human brain penetration. Preclinical species are used as in vivo models to understand the unbound brain exposure by deriving the Kp,uu parameter, the brain/plasma ratio of exposure corrected with the plasma and brain free fraction. MDCK-mdr1 (Madin Darby canine kidney cells transfected with the MDR1 gene encoding for the human P-gp) assay is the most commonly used in vitro assay to estimate compound permeability and human efflux. The in silico methods to predict brain exposure, such as CNS MPO, CNS BBB scores and various Machine Learning models, help save costs and speed up compound discovery and optimization at all stages. These methods enable the screening of virtual compounds and building of a CNS penetrable compounds library as well as optimization of lead molecules for CNS penetration. Therefore, it is crucial to understand these methods' reliability and ability to predict CNS penetration. We review the in silico, in vitro and in vivo data and their correlation with each other and assess published in silico approaches to predict the BBB penetrability of compounds.
Keywords
The Blood-Brain Barrier (BBB); CNS drug discovery; passive diffusion; active transport; Efflux transporters; Influx Transporters; P-glycoproteins (P-gp); breast cancer resistance protein (BCRP); in silico models
Subject
Medicine and Pharmacology, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
