Computational elucidation of allosteric communication in proteins for allosteric drug design

Allosteric modulators target topologically distal allosteric sites in order to modulate orthosteric sites, providing enhanced specificity and physiochemical properties. Harnessing allostery for drug discovery is an emerging paradigm in modern pharmaceutics. Allosteric regulation substantially depends on the propagation of allosteric signaling. Delineating allosteric signaling pathways is therefore one of the leading prerequisites for allosteric drug discovery. Allosteric signal transduction is subtle and dynamic, posing challenges for characterization through traditional experimental techniques, but computational strategies promise to provide a solution to this problem. Here, we comprehensively review bioinformatic methods for elucidating allosteric communication, along with their successful applications in allosteric drug design. Current challenges and future perspectives are also discussed. We aim to provide guidance for the future application and optimization of these computational strategies, thereby promoting rational allosteric drug discovery.