Advancements in Computer-Aided Drug Design: Targeting the PD-1/PD-L1 Immune Checkpoint with Small Molecule Inhibitors

Cancer continues to be a major global health burden, with conventional therapies often limited by relapse, resistance, and toxicity. Immunotherapy, particularly PD-1/PD-L1 checkpoint blockade, has transformed treatment by reactivating antitumor T-cell responses. While monoclonal antibodies against PD-1/PD-L1 have shown remarkable success, their high cost, intravenous delivery, immune-related side effects, and resistance highlight the need for alternatives. Small molecule inhibitors (SMIs) offer advantages such as oral bioavailability, improved tumor penetration, reduced immunogenicity, and lower production costs. However, the broad PD-1/PD-L1 interface poses design challenges. Recent advances in computer-aided drug design (CADD)—including docking, pharmacophore modeling, QSAR, virtual screening, and in silico ADME/T prediction—are driving progress in developing effective SMIs. This review outlines the biology of the PD-1/PD-L1 axis, the evolution of checkpoint therapy, and current efforts to harness CADD for novel small molecule inhibitors.