4 research outputs found
Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators
Ribonucleotide
reductase (RR) catalyzes the rate-limiting step of dNTP synthesis
and is an established cancer target. Drugs targeting RR are mainly
nucleoside in nature. In this study, we sought to identify non-nucleoside
small-molecule inhibitors of RR. Using virtual screening, binding
affinity, inhibition, and cell toxicity, we have discovered a class
of small molecules that alter the equilibrium of inactive hexamers
of RR, leading to its inhibition. Several unique chemical categories,
including a phthalimide derivative, show micromolar IC<sub>50</sub>s and <i>K</i><sub>D</sub>s while demonstrating cytotoxicity.
A crystal structure of an active phthalimide binding at the targeted
interface supports the noncompetitive mode of inhibition determined
by kinetic studies. Furthermore, the phthalimide shifts the equilibrium
from dimer to hexamer. Together, these data identify several novel
non-nucleoside inhibitors of human RR which act by stabilizing the
inactive form of the enzyme