Predicting Regioselectivity of Cytosolic Sulfotransferase Metabolism for Drugs.

Cytosolic sulfotransferases (SULTs) are a family of enzymes responsible for the sulfation of small endogenous and exogenous compounds. SULTs contribute to the conjugation phase of metabolism and share substrates with the uridine 5'-diphospho-glucuronosyltransferase (UGT) family of enzymes. UGTs are considered to be the most important enzymes in the conjugation phase, and SULTs are an auxiliary enzyme system to them. Understanding how the regioselectivity of SULTs differs from that of UGTs is essential from the perspective of developing novel drug candidates. We present a general ligand-based SULT model trained and tested using high-quality experimental regioselectivity data. The current study suggests that, unlike other metabolic enzymes in the modification and conjugation phases, the SULT regioselectivity is not strongly influenced by the activation energy of the rate-limiting step of the catalysis. Instead, the prominent role is played by the substrate binding site of SULT. Thus, the model is trained only on steric and orientation descriptors, which mimic the binding pocket of SULT. The resulting classification model, which predicts whether a site is metabolized, achieved a Cohen's kappa of 0.71.