Role of Molecular Recognition in L-Cystine Crystal Growth Inhibition

L-Cystine kidney stones aggregates of single crystals of the hexagonal form of L-eystine afflict more than 20000, individuals in the United States alone. Current therapies are often ineffective and produce adverse side effects. Recognizing that the growth. of L-cystirie crystals is a critical step in stone pathogenesis, real-time in situ atomic force microscopy of growth on the (0001) face of L-cystine crystals and measurements of crystal growth anisotropy were performed in the presence of prospective inhibitors drawn from a 31-member library. The most effective. molecular imposters for crystal growth inhibition were L-cystine mimics (aka molecular imposters), particularly L-cystine diesters and diamides, for which a kinetic analysis revealed a common inhibition mechanism consistent with Cabrera-Vermilyea step pinning. The amount of inhibitor incorporated by L-cystine crystals', estimated from kinetic data, suggests that imposter binding to the {0001} face is less probable than binding of L-cystine solute molecules, whereas imposter binding to {10 (1) over bar0} faces is comparable to that of L-cystine molecules. These estimates were corroborated by computational binding energies. Collectively, these findings identify the key structural factors responsible for molecular recognition between molecular imposters and L-cystine, crystal kink sites,,and the inhibition of crystal growth: The observations are consistent with the-reduction of L-cystine stone burden in mouse models by the more effective inhibitors, thereby articulating a strategy for stone prevention based on molecular design.