In Silico Methods to Assess CNS Penetration of Small Molecules

• DOI: 10.20944/preprints202401.1443.v1
• Publication Date: 2024-01-23T07:21:06Z
• Authors: Mayuri Gupta; Jun Feng; Govinda Bhisetti
• Keywords: Penetration (warfare)

In CNS drug discovery, estimation of brain exposure lead compounds is critical for their optimization. Compounds need to cross the blood-brain barrier (BBB) reach pharmacological targets in CNS. The BBB a complex system involving passive and active mechanisms transport efflux transporters such as P-glycoproteins (P-gp) breast cancer resistance protein (BCRP), which play an essential role penetration small molecules. Several vivo, vitro silico methods are available estimate human penetration. Preclinical species used vivo models understand unbound by deriving Kp,uu parameter, brain/plasma ratio corrected with plasma free fraction. MDCK-mdr1 (Madin Darby canine kidney cells transfected MDR1 gene encoding P-gp) assay most commonly compound permeability efflux. predict exposure, MPO, scores various Machine Learning models, help save costs speed up discovery optimization at all stages. These enable screening virtual building penetrable library well molecules Therefore, it crucial these methods' reliability ability We review silico, data correlation each other assess published approaches penetrability compounds.