Hybrid 2D/3D-quantitative structure-activity relationship and modeling studies perspectives of pepstatin A analogs as cathepsin D inhibitors.

Abstract

Cathepsin D, one of the attractive targets in the treatment of breast cancer, has been implicated in HIV neuropathogenesis with potential proteolytic effects on chemokines. Methodology/result: Diverse modeling tools were used to reveal the key structural features affecting the inhibitory activities of 78 pepstatin A analogs. Analyses were performed to investigate the stability, rationality and fluctuation of the analogs. Results showed a clear correlation between the experimental and predicted activities of the analogs as well as the variation in their activities relative to structural modifications. The insight gained from this study offers theoretical references for understanding the mechanism of action of cathepsin D and will aid in the design of more potent and clinically-relevant drugs. Graphical abstract [Formula: see text].