Drug delivery to specific ocular tissues is a major challenge because the factors required for the uptake and ocular distribution of drugs remains largely undefined. Molecular descriptors are increasingly being used to define and model the pharmacological I pharmacokinetic properties of drugs. This proposal introduces a new approach to ocular drug delivery and distribution by establishing that specific molecular descriptors on a drug can be used to """"""""guide"""""""" a molecule to its specific ocular target tissue. This is based on our finding that select molecular attributes I descriptors appear to guide the uptake and distribution of orally administered multifunctional antioxidants (MFAOs) synthesized in our laboratory into the lens, neural retina, and brain. This proposal seeks to expand on this initial observation with 6 MFOAs by expanding the study to 24 compounds that include the parent and mono- functional analogs. Molecular attributes/descriptors will be obtained using Molecular Operating Environment (MOE) software as well as Volsurf software that is especially designed for optimizing in silico pharmacokinetic properties. These will be correlated with drug levels obtained in the cornea, iris/ciliary body, lens, neural retina and the remaining posterior segment (RPE, choroid, sclera) of adult rat eyes as well as brain, liver, kidney, and peripheral (sciatic) nerve. The correlations established in the in vivo quantitative structure activity relationship (QSAR) model will be validated by the subsequent evaluation of test compounds that are designed from the model and then synthesized and evaluated in rats. The validated model will not only allow us to predict the tissue uptake of MFAOs, but will also establish a model for predicting the tissue uptake of other drugs based on their molecular attributes / descriptors.
This proposal introduces a new approach to ocular drug delivery and distribution by establishing that specific molecular descriptors on a drug can be used to guide the drug to its specific ocular target tissue. A quantitative in vivo structure activity relationship (QSAR) model will be developed by correlating molecular attributes / descriptors of systemically administered multifunctional antioxidants to their uptake and distribution into the cornea, iris/ciliary body, lens, neural retina and the remaining posterior segment (RPE, choroid, sclera) of adult rat eyes as well as brain, liver, kidney, and peripheral (sciatic) nerve.
