Over the past few years, immunotherapy has been associated with significant results in cancer treatment. By modulating the activity of T-cells, activating apoptosis of antigen-specific T-cells, and inhibiting regulatory T-cell activity, Programmed Cell Death Protein 1 (PD-1) inhibits immune responses and promotes self-tolerance. A transmembrane protein called Programmed Cell Death Ligand 1 (PD-L1), in association with PD-1, can inhibit cytokine secretion and suppress the proliferation of PD-1-positive cells. In various malignancies, PD-L1 can attenuate the host immune response against tumor cells. Proceeding from the above, it can be assumed that PD-1/PD-L1 contributes to cancer immune escape and greatly affects cancer treatment.
Our new PD-L1 Targeted Screening Library contains over 2,000 structurally diverse screening compounds. Their ability to disrupt protein-protein interactions (PPI) between PD-1/PD-L1 was explored by receptor-based virtual screening (molecular docking) of the Life Chemicals HTS Compound Collection comprising over 510,000 proprietary small molecules.
The compound selection can be customized based on your requirements, cherry picking is available.
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Compound selection procedure:
To start with, all toxic, reactive, and pan-assay interference compounds (PAINS) were filtered out. Since many PPI inhibitors were shown to be non-compliant with the "Rule of Five (Ro5)" owing to their physicochemical criteria, upper thresholds for Ro5 were not limited.
Taking into account recent publications  and relevant X-ray data, we decided to conduct two separate virtual screens, since the binding site adopts two different conformations (open and closed) depending on the ligand bound (Fig. 1). Multiple conformations were used with the purpose to increase the accuracy of the docking, and thus, the hit rate.
Figure 1. PPI interface and conformational differences in PD-L1 . Amino acid residues of the ligand-binding site are labeled.
According to , two PDB entries 5N2D and 5N2F have been taken and prepared for the virtual screening. Their receptor grids were constructed without assigning any constraints, such as H-bond and hydrophobic regions, in order to allow the software to explore as many positions and conformations in the PPI interface as possible. Rotatable groups in the residues that could make contacts with the docked ligands were allowed.
Figure 2. Examples of receptor-ligand complexes obtained with PD-L1 docking. A: 5N2F and F2057-0496 B: 5N2D and F2057-0496
High-Throughput Virtual Screening (HTVS) and Standard Precision docking (SP) implemented in the Glide (Schrödinger) program were applied sequentially for each screen. After docking with both HTVS and SP, the compounds obtained were ranked by the docking score and presence of strong intermolecular interactions in order to select top virtual hits with potential PPI inhibitory activity (Fig. 2). As a result, over 2,000 best-scored screening molecules have been selected and included in this Screening Set to become a very attractive and potent tool for early-stage drug discovery.
1. Guzik K, Zak KM, Grudnik P, Magiera K, Musielak B, Törner R, Skalniak L, Dömling A, Dubin G, Holak TA. Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1. J Med Chem. 2017, 60(13):5857-5867.