Molecular modeling studies of Indoline Scaffold derivatives as PD‐1/PD‐L1 pathway inhibitors by QSAR, molecular docking and molecular dynamics simulation techniques

Abstract

In recent years, blocking the interaction of programmed cell death receptor‐1 (PD‐1) and programmed cell death ligand‐1 (PD‐L1) has been recognized as one of the promising cancer therapies. Due to the many limitations of monoclonal antibodies, the development of small molecule inhibitors targeting PD‐1/PD‐L1 is imminent. This study aims to systematically investigate the interaction mechanisms of novel PD‐1/PD‐L1 inhibitors containing indoline backbone structures using 3D/2D‐QSAR modeling, molecular docking, molecular dynamics (MD) simulation, and ADMET prediction. The performance and predictive ability of the constructed QSAR models were evaluated by internal and external validation techniques. Topomer CoMFA and HQSAR models showed good reliability and predictive capability. By searching for R‐groups in the Topomer search module and combining the existing molecules with high activity contribution values, 24 new compounds with theoretically high activity were obtained, which showed desirable docking scores, appropriate ADMET properties, and good stability. This work not only provides a reliable QSAR model as a valuable screening tool for the development of future drugs targeting PD‐1/PD‐L1, but also makes the newly designed inhibitors expected to be potential PD‐1/PD‐L1 inhibitors that can be used for further synthesis and characterization to obtain novel anti‐cancer drugs targeting PD‐1/PD‐L1.