Understanding a drug candidate's pharmacokinetic (PK) parameters is a challenging but essential aspect of drug development. Investigating the penetration and distribution of a topical drug's active pharmaceutical ingredient (API) allows for evaluating drug delivery and efficacy, which is necessary to ensure drug viability. A topical gel (BPX-05) was recently developed to treat moderate to severe acne vulgaris by directly delivering the combination of the topical antibiotic minocycline and the retinoid tazarotene to the pilosebaceous unit of the dermis. In order to evaluate the uptake of APIs within human facial skin and confirm accurate drug delivery, a selective visualization method to monitor and quantify local drug distributions within the skin was developed. This approach uses fluorescence lifetime imaging microscopy (FLIM) paired with a multicomponent phasor analysis algorithm to visualize drug localization. As minocycline and tazarotene have distinct fluorescence lifetimes from the lifetime of the skin's autofluorescence, these two APIs are viable targets for distinct visualization via FLIM. Here, we demonstrate that the analysis of the resulting FLIM output can be used to determine local distributions of minocycline and tazarotene within the skin. This approach is generalizable and can be applied to many multicomponent fluorescence lifetime imaging targets that require cellular resolution and molecular specificity. open Scientific RepoRtS | (2020) 10:5360 | https://doi.

However, there are no highthroughput functional assays for σ 1 receptor drug discovery. Here, we assessed high-throughput structure-based computational docking for discovery of novel ligands of the σ 1 receptor. We screened a library of over 6 million compounds using the Schrodinger Glide package, followed by experimental characterization of top-scoring candidates. 77% of tested candidates bound σ 1 with high affinity (K D < 1 μM). These include compounds with high selectivity for the σ 1 receptor compared to the genetically unrelated but pharmacologically similar σ 2 receptor, as well as compounds with substantial crossreactivity between the two receptors. These results establish structure-based virtual screening as a highly effective platform for σ 1 receptor ligand discovery and provide compounds to prioritize in studies of σ 1 biology.