Design of Biphenyl‐Type Programmed Cell Death‐Ligand 1 Inhibitors Using 3D‐QSAR, Molecular Docking, and Molecular Dynamics Simulation

Abstract Blocking the interaction between programmed cell death‐1 (PD‐1) and programmed cell death‐ligand 1 (PD‐L1) is a crucial immunotherapeutic strategy for cancer. Currently, all inhibitors available on the market that target PD‐1/PD‐L1 are monoclonal antibodies, with no small molecule drugs yet accessible. This study focused on PD‐L1 and conducted three‐dimensional quantitative structure‐activity relationship (3D‐QSAR) research on 39 PD‐L1 inhibitors using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The CoMFA (q 2 =0.593, r 2 =0.991) and CoMSIA (q 2 =0.542, r 2 =0.971) models were successfully established. Based on these models, a series of structurally novel and potentially active PD‐L1 inhibitors ( 37 a – 37 e ) were designed. Among these compounds, 37 c exhibited superior performance, with CoMFA predicting a pIC 50 value of 9.204 and CoMSIA predicting a pIC 50 value of 8.597. Further molecular docking and molecular dynamics simulations revealed that compound 37 c establishes hydrophobic interactions with B Tyr56 and B Val68 of PD‐L1, engages in hydrogen bonds with A Asp122, A Lys124, and B Tyr123, and forms electrostatic interactions with A Lys124 and A Met115. The design of this biphenyl series of inhibitors offers additional options for the development of small molecule inhibitors targeting PD‐L1, with 37 c expected to be a promising inhibitor of PD‐L1.