title: High-Throughput Melanin-Binding Affinity and In Silico Methods to Aid in the Prediction of Drug Exposure in Ocular Tissue.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Cambridge, Massachusetts 02139. Electronic address: john.reilly@novartis.com.
authors.forename: John
authors.initials: J
authors.lastname: Reilly
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Cambridge, Massachusetts 02139.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Williams
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Cambridge, Massachusetts 02139.
authors.forename: Cornelia J
authors.initials: CJ
authors.lastname: Forster
authors.affiliation: Novartis Institutes for BioMedical Research, Ophthalmology, Cambridge, Massachusetts 02139.
authors.forename: Viral
authors.initials: V
authors.lastname: Kansara
authors.affiliation: Novartis Institutes for BioMedical Research, DMPK, Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: End
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Cambridge, Massachusetts 02139.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
mesh_terms: D003198:Computer Simulation; D005123:Eye / Q000378:metabolism*; D008543:Melanins / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D008543:Melanins; D004364:Pharmaceutical Preparations
keywords: QSAR; affinity chromatography; bioanalysis; in-vitro-in-vivo correlation (IVIVC); distribution; in silico; ocular PK; melanin; modeling; pharmacokinetics