SMYD3 has been characterized as a versatile lysine methyltransferase, and is associated with multiple types of cancer, including colorectal, liver, and breast cancer. A range of histone and non-histone protein substrates are lysine N-methylated by methyl transfer from the SAM cofactor of SMYD3. Notably, loss of SMYD3 catalytic activity inhibited tumorigenesis in the presence of oncogenic Ras 1 , suggesting that inhibition of SMYD3 in cancers with elevated RAS pathway signalling may be a useful therapeutic strategy. However, few SMYD3 inhibitors have been reported . GSK has previously reported a crystal structure of the ternary complex of SMYD3, SAH and MEKK2 and a second crystal structure showing GSK2807 binding in the SAM pocket . More recently, the identification and optimisation of a series of isoxazole amides as SMYD3 inhibitors was reported . The ability of computational binding free energy calculations to predict the affinity of that series of ligands is presented here.