Understanding the variability of the S1′ pocket to improve matrix metalloproteinase inhibitor selectivity profiles

Matrix metalloproteinases (MMPs) are a family of proteins involved in a range of pathologies. Given that MMP broad-spectrum inhibition is associated with severe adverse effects, selectivity has become a priority in the design of MMP inhibitors, and is often achieved by targeting the variable S1′ pocket. However, the specific characteristics of the S1′ pocket that determine inhibitor selectivity are often not described and, in many cases, challenging to identify. In this review, we investigate the variability of the S1′ pocket across the MMP family, and propose explanations for the selectivity of previously described inhibitors. These analyses provide valuable insights into how to design novel inhibitors selective for a given MMP.