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.