The Discovery of Cryptic Pockets Increases the Druggability of “Undruggable” Proteins

The absence of suitable biological targets is one of the most formidable obstacles to drug development. The investigation of "undruggable" proteins has the potential to significantly increase the druggable proteome. Cryptic pockets represent specific potential pockets that provide a rare opportunity to target "undruggable" proteins. The identification of cryptic pockets, in combination with drug design studies, has made significant progress, especially due to the emergence of artificial intelligence (AI) technology. However, there has been no comprehensive review of the methods and successful identification of cryptic pockets and associated inhibitors for "undruggable" targets. Here, we systematically summarize and analyze the latest strategies for identifying cryptic pockets and designing related inhibitors. First, we analyze both computational methods and experimental approaches for the discovery of cryptic pockets or regions. We will also discuss studies that have successfully identified specific cryptic pockets and developed compounds that inhibit the "undruggable" targets, using these as successful case studies. The limitations, drawbacks, and underlying trends in cryptic pocket identification and inhibitor design will also be discussed. We anticipate that this article will guide biologists and chemists in efficiently and accurately identifying cryptic pockets present in "undruggable" targets to facilitate relevant drug discovery.