Author:
Dey Debabrata,Nunes-Alves Ariane,Wade Rebecca C,Schreiber Gideon
Abstract
AbstractCrowded environments affect the pharmacokinetics of drug molecules. Here, we investigate how three macromolecular protein crowders, bovine serum albumin, hen egg-white lysozyme and myoglobin, influence the translational diffusion rates and interactions of four low molecular-weight drugs, fluorescein, doxorubicin, glycogen synthase kinase-3 inhibitor SB216763 and quinacrine. Using Fluorescence Recovery After Photo-bleaching in Line mode (Line FRAP), Brownian dynamics simulations and molecular docking, we find that the diffusive behavior of the small molecules is highly affected by self-aggregation, interactions with the proteins, and surface adhesion. Fluorescein diffusion is decreased by protein crowders due to their interactions. On the other hand, for doxorubicin, the presence of protein crowders increases diffusion by reducing surface interactions. SB216763 shows a third scenario, where BSA, but not myoglobin or lysozyme, reduces self-aggregation, resulting in faster diffusion. Quinacrine was the only small molecule whose diffusion was not affected by the presence of protein crowders. The mechanistic insights gained here into the effects of interactions of small molecules with proteins and surfaces on the translational diffusion of small molecules can assist in optimizing the design of compounds for higher mobility and lower occlusion in complex macromolecular environments.Significance statementThe activity of small molecules is directly related to their active concentration. This, in turn, relates to their molar concentration and their activity coefficient. Any deviations from ideal behavior affects the small molecule activity. This is particularly important for drugs, where we seek to optimize their molar activity. Here, we follow the diffusional activity of four small molecule drugs in various solutions, with and without protein crowders. The study, which involves experimental measurements and theoretical simulations, shows that 3 of the 4 drugs do not diffuse normally, either due to aggregation, protein binding or surface adhesion. We show the mechanisms driving the abnormal diffusion, and how it can be reduced. Lessons learned from this study can be implemented into drug design.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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