Cellular co-factors provide a convenient, but challenging entry point for the design of small molecules that modulate the activity of novel biological targets. For example, we are currently focussed on developing modulators of protein arginine methyltransferases (PRMTs) since they may have a defining role in epigenetic regulation of cell status. This talk will outline our development of potential PRMT inhibitors designed to occupy binding sites for the co-factor AdoMet and the arginine protein substrate, some of which were found to discriminate between two PRMT enzyme family members, PRMT1 and CARM1.
[Fig.] That the molecule above inhibits PRMT1 but not CARM1 may be explained by a key difference in respective amino acids at the binding site, specifically an electrostatic interaction with Glu47 (PRMT1, salmon), but not Asn162 (CARM1, green). Docking and overlay reveals the inhibitor occupying both co-factor site and substrate channels (blue mesh) close to these divergent amino acids