The WD40 repeat (WDR) domain is one of the most abundant protein-protein interactions (PPIs) domains in the human proteome. PPI’s have pivotal roles in many cellular processes and many diseases are a result of perturbed PP’s3. Antagonism of PPIs with small molecules is becoming a more feasible therapeutic approach, with the recent approval of PPI inhibitory drugs such as venetoclax (a BCL2--BAX antagonist) and continued clinical research into others such as the BET bromodomain antagonists4. Recently, chemical probes targeting two WDR proteins have been successfully designed. This novel class of protein is now under investigation globally for their involvement in critical biological processes and human diseases.<br/>Chemical probes need to be potent, selective and cell-permeable inhibitors of protein function and are valued reagents in both fundamental and applied biological research. The search is on for chemical probes that are selective for specific WDRs to drive understanding of these understudied target class.<br/>MatchMaker is a deep learning approach capable of assessing small molecule-protein interactions across the proteome. To discover novel WDR binders, the interaction profiles of approximately 3million commercially available compounds with ~8,500 proteins were rapidly predicted using Cyclica’s MatchMaker technology. This allows for selection of compounds based not only on predicted binding, but also on the lack of interaction with undesirable off-targets. Using MatchMaker predictions, alongside traditional CADD tools, we predicted and experimentally validated multiple hits for several novel WDR proteins.

Designing chemical probes for WD40 repeat proteins using MatchMakerTM

ACS Fall 2021

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