High-Throughput Melanin-Binding Affinity and In Silico Methods to Aid in the Prediction of Drug Exposure in Ocular Tissue.
Drugs possessing the ability to bind to melanin-rich tissue, such as the eye, are linked with higher ocular exposure, and therefore have the potential to affect the efficacy and safety profiles of therapeutics. A high-throughput melanin chromatographic affinity assay has been developed and validated, which has allowed the rapid melanin affinity assessment for a large number of compounds. Melanin affinity of compounds can be quickly assigned as low, medium, or high melanin binders. A high-throughput chromatographic method has been developed and fully validated to assess melanin affinity of pharmaceuticals and has been useful in predicting ocular tissue distribution in vivo studies. The high-throughput experimental approach has also allowed for a specific training set of 263 molecules for a quantitative structure-affinity relationships (QSAR) method to be developed, which has also been shown to be a predictor of ocular tissue exposure. Previous studies have reported the development of in silico QSAR models based on training sets of relatively small and mostly similar compounds; this model covers a broader range of melanin-binding affinities than what has been previously published and identified several physiochemical descriptors to be considered in the design of compounds where melanin-binding modulation is desired.
['Reilly|John|J|', 'Williams|Sarah L|SL|', 'Forster|Cornelia J|CJ|', 'Kansara|Viral|V|', 'End|Peter|P|', 'Serrano-Wu|Michael H|MH|']
D003198:Computer Simulation D005123:Eye D008543:Melanins D004364:Pharmaceutical Preparations D021281:Quantitative Structure-Activity Relationship
in silico melanin distribution QSAR modeling affinity chromatography bioanalysis in-vitro-in-vivo correlation (IVIVC) ocular PK pharmacokinetics