Targeting cryptic-orthosteric site of PD-L1 for inhibitor identification using structure-guided approach

by Selleckchem | Sep 03 2023

Approved mAbs that block the protein-protein interaction (PPI) interface of the PD-1/PD-L1 immune checkpoint axis have led to significant improvements in cancer treatment. Despite having drawbacks of mAbs only few a compounds are reported till date against this axis. Inhibiting PPIs using small molecules has emerged as a significant therapeutic opportunity, demanding for the identification of drug-like molecules at an accelerated pace under the hit-to-lead campaigns. Due to the PD-L1's cross-talk with PD-1/CD80 and its overexpression on cancer cells, as well as the availability of its crystal structures with small molecules, it is an enticing therapeutic target for structure-assisted small molecule design. Furthermore, the selection of chemical databases enriched with focused designing for PPI interfaces is crucial. Therefore, in this study we have utilized the Asinex signature library for structure-assisted virtual screening to find the potential PD-L1 inhibitors by targeting the cryptic PD-L1 interface, followed by induced fit docking for pose refinements in the pocket. The obtained hits were then subjected to interaction fingerprinting and ligand-based drug-likeness investigations in order to evaluate and analyze their drug-like qualities (ADME). Twelve compounds qualified for molecular dynamics simulations, followed by thermodynamic calculations for evaluation of their stability and energetics inside the pocket. Two novel compounds with different chemical moieties have been identified that are consistent throughout the simulation, mimicking the interactions and binding energies with BMS-1166. These compounds appear as potential therapeutic candidates to be explored experimentally, thereby paving the way for the development of novel leads as immunomodulators.

Comments:

The study you described focused on utilizing structure-assisted virtual screening and molecular dynamics simulations to identify potential small molecule inhibitors of the PD-L1 protein-protein interaction (PPI) interface. The PD-1/PD-L1 immune checkpoint axis is an important target in cancer treatment, and while monoclonal antibodies (mAbs) have shown success in blocking this interaction, there is a need for additional compounds, particularly small molecules.

The researchers in this study used the Asinex signature library for virtual screening to identify potential PD-L1 inhibitors. They targeted the cryptic PD-L1 interface, which is involved in the interaction with PD-1/CD80. The initial hits obtained from virtual screening were further refined using induced fit docking to improve the pose of the compounds in the binding pocket.

To evaluate the drug-like qualities of the hits, the researchers performed interaction fingerprinting and ligand-based drug-likeness investigations. These analyses help assess the potential of the compounds to function as drugs by considering factors such as their interactions with the target and their pharmacokinetic properties (ADME - absorption, distribution, metabolism, and excretion).

Twelve compounds were selected based on their favorable drug-like qualities for further investigation using molecular dynamics simulations. These simulations allowed the researchers to study the stability and energetics of the compounds inside the binding pocket over time. By evaluating the interactions and binding energies of the compounds throughout the simulations, two novel compounds with different chemical moieties were identified as potential therapeutic candidates. These compounds consistently mimicked the interactions and binding energies observed with BMS-1166, a known PD-L1 inhibitor.

The findings of this study suggest that these two novel compounds could be promising leads for further experimental exploration as immunomodulators targeting the PD-L1 protein-protein interaction. The combination of structure-assisted virtual screening, molecular dynamics simulations, and thermodynamic calculations enabled the identification and evaluation of these potential drug candidates, potentially paving the way for the development of novel immunomodulatory therapies.