High-throughput virtual screening of small-molecule inhibitors targeting immune cell checkpoints to discover new immunotherapeutics for human diseases.

Immunotherapy is widely used to treat various cancers, and the drugs used are called immune checkpoint (ICP) inhibitors. Overexpression of immune cell checkpoints is reported for other human diseases such as acute infections (malaria), chronic viral infection (HIV, hepatitis B virus, TB infections), allergy, asthma, neurodegeneration, and autoimmune diseases. Some mAbs (monoclonal antibodies) are available against ICPs, but they have side effects. Small molecule seems to be safer in comparison with mAbs. Three independent small-molecule inhibitor libraries consisting of 9466 compounds were screened against seven immune cell checkpoints by applying high-throughput virtual screening approach. A total of 13 ICP inhibitors were finalized based on docking, MM-GBSA scores, and ADME properties. Six compounds were selected for MD simulation, and then, rutin hydrate (targeting all seven immune cell checkpoints), amikacin hydrate (targeting six), and 6-hydroxyluteolin (targeting three) were found to be the best immune cell checkpoint inhibitors. These three potential inhibitors have shown the potential to activate human immune cells and thus may control the spread of human lifestyle or infectious diseases. Proposed inhibitors warrant the in vitro and in vivo validation to develop it as an immunotherapeutic.