RORγ Library is comprised of approximately 13,000 compounds. RORγ, a nuclear receptor, serves as a master regulator of Th17 cell development, making it an appealing target for the treatment of autoimmune diseases. The significance and interest in RORγ as a therapeutic target is evident from the large number of publications indexed in the PubMed database, with more than 500 publications since 2019. The PDB database has also seen significant contributions, with more than 32 newly deposited structures related to RORγ since 2019. Furthermore, there are over 4,000 associated bioactivities recorded in the ChEMBL database.
The design strategy for the RORγ Library takes into account the lipophilic nature of RORγ’s binding site. It is crucial to avoid compounds that have high lipophilicity and sub-optimal Absorption, Distribution, Metabolism, and Excretion (ADME) properties. However, a minimum level of LogD (the logarithm of the distribution coefficient) is still necessary for activity.
The design approach includes the following steps:
“LogD control”: Compounds in the library are selected to fall within the logD range of 2-5, ensuring a balance between lipophilicity and activity.
Structure-based design using high-quality crystal structures: Utilizing well-resolved crystal structures, the design process is guided by the molecular features of the binding site.
To construct the library, around 700,000 compounds were initially selected using medicinal chemistry filters and clogD criteria. Molecular docking, facilitated by the ICM docking engine, was performed to focus the screening library to approximately 170,000 compounds. High-precision docking using Flare5 software further refined the selection, resulting in 50,000 compounds with top scores. A diversity picking process was then applied to select a final set of 13,000 compounds representing a diverse range of chemical structures.
Detailed information regarding the basic physicochemical properties and representative structures of the library can be found in the accompanying slides. This comprehensive design strategy ensures that the RORγ Library comprises a high-quality collection of compounds suitable for further exploration as potential therapeutics for autoimmune diseases.
