Modifiers of Calcium Oxalate Monohydrate Crystallization: Elucidating Modifier-crystal Interactions for Rational Drug Design

Calcium oxalate monohydrate (COM) crystals are the primary constituent of human kidney stones. The growth of these crystals in vivo is affected by different urinary constituents (e.g., ions and molecules), which act as modifiers by adsorbing onto different sites of the crystal surface, thereby influencing the rates of anisotropic crystal growth that concomitantly alter properties such as size and habit.[1] At the molecular level, COM crystals grow classically (i.e. monomer-by-monomer addition) where single layers nucleate and advance across the surface by solute addition to surfaces sites (e.g. kinks, steps, or terraces).[2] Introduction of modifiers to crystal growth solutions can alter the kinetics and thermodynamics of such processes through adsorption onto surfaces sites which can block solute incorporation, or by complexing with free monomers in solution that can affect supersaturation (i.e., the primary driving force for crystal growth).[3,4] We conducted systematic bulk crystallization measurements to assess the performance of different COM growth modifiers. We assessed their effects on crystal size and habit, which allowed for the identification of modifiers that preferentially bind to specific crystallographic faces. Similarly, we classified modifiers as either growth promoters or inhibitors using in situ ion selective electrochemistry (ISE) as a function of modifier concentration. The majority of modifiers act as inhibitors; however, a few modifiers have been identified as being growth promoters. To gain insight on the molecular events that facilitate growth modification, we use in situ atomic force microscopy (AFM) to systematically probe the effect of naturally occurring and synthetic modifiers on the dynamics of surface growth. Our studies reveal unique modes of modifier action that vary significantly with subtle changes in the physicochemical properties of the modifier. Here, we will present our results demonstrating how these techniques serve as a useful platform for the design of new generation therapeutics to treat pathological diseases, such as kidney stones.

1. Farmanesh S, Alamani BG, Rimer JD Identifying alkali metal inhibitors of crystal growth: A selection criterion based on ion pair hydration energy. Chemical Communications
2015 51:13964-13967.
2. Chung JH, Granja I, Taylor MG, Mpourmpakis G, Asplin JR, Rimer JD Molecular modifiers reveal a mechanism of pathological crystal growth inhibition. Nature 2016 536:446-+.
3. Olafson KN, Li R, Alamani BG, Rimer JD Engineering crystal modifiers: Bridging classical and nonclassical crystallization. Chem Mater 2016
4. Alamani BG, Rimer, J. D. Molecular modifiers of kidney stones. Curr Opin Nephrol Hy 2017