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Computational methods in medicinal chemistry facilitate drug discovery and design. In particular, machine learning methodologies have recently gained increasing attention. This chapter provides a structured overview of the current state of computational chemistry and its applications for the interrogation of the endocannabinoid system (ECS), highlighting methods in structure-based drug design, virtual screening, ligand-based quantitative structure-activity relationship (QSAR) modeling, and de novo molecular design. We emphasize emerging methods in machine learning and anticipate a forecast of future opportunities of computational medicinal chemistry for the ECS., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Peroxisome proliferator-activated receptors are a family of nuclear hormone receptors that control the expression of genes involved in a variety of physiologic processes, through heterodimerization with retinoid X receptor and complex formation with various cofactors. The specific cofactors recruited to PPAR-RXR complexes in response to different ligands lead to major differences in the transactivation of target genes. We developed a cofactor recruitment assay that is based on an europium-labeled anti-GST antibody and streptavidin-APC leading to a fluorescence resonance energy transfer signal. This assay allows for the determination of unique agonistic profiles in terms of potency and co-activator motif. Hence, it is a valuable drug discovery tool to support hit finding and lead optimization campaigns, enabling the characterization of next generation PPAR agonists., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Peroxisome proliferator-activated receptors (PPARs) have been exploited as drug targets for combating multiple diseases. Several activators with different selectivity for the PPAR α, γ, and δ subtypes have been introduced into the market or have reached advanced clinical trials. Binding assays are of utmost importance for the discovery and profiling of such PPAR ligands. Binding assays are often based on radioligands, in particular, tritiated molecules are applied. We developed synthetic procedures for tritiating various PPAR agonists and applied these radioligands for setting up a scintillation proximity assay (SPA) for PPAR α, γ, and δ. These SPAs allow to assess the binding affinities of PPAR α, γ, and δ ligands, along with their respective subtype selectivity profiles. Therefore, SPA is an important tool for hit discovery and lead optimization campaigns aimed at identifying next-generation PPAR ligands., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)