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- W2793043164 abstract "How does one design a small-molecule ligand for a disordered protein (IDP)? Typical structure-based drug design approaches are not applicable to IDPs, since most regions of IDPs do not possess specific structures in physiological conditions. This is a critical problem, since many IDPs are associated with serious human diseases (such as Alzheimer's and Parkinson's). Here we propose that drug discovery in such cases can rely on the intrinsic fluctuations of the disordered protein. Even transiently interacting small molecules will likely leave their imprint on this dynamics, and the degree of perturbation can be used as an assay for narrowing down the chemical search space for candidate drug molecules. We demonstrate this approach for hIAPP (amylin), an IDP associated with Type II diabetes, using a home-built fluorescence cross correlation spectrometer (FCCS). The intrinsic fluctuations can be studied using FRET using a donor (D) at the C-terminal and a quencher (A) at the N-terminal. The donor blinks as the D-A separation changes due to spontaneous fluctuations, and the time scale of this bright-dark transition is 137.5 ± 5.1 ns. This varies linearly with the viscosity of the medium, as is expected for intra-chain diffusion. Zn++, which is known to interact with hIAPP, does not induce any change in the dynamics. However, some other reagents which have been suggested to interact with amylin (mentioned below), do alter the dynamics significantly. Our fluctuation based scoring yields the following order for the strength of interaction: quercetin ≈ epicatechin > EGCG > congo red. We infer that it is possible to quantitatively measure the degree of transient interactions of small molecules with an IDP, even when no particular structure is formed as a result." @default.
- W2793043164 created "2018-03-29" @default.
- W2793043164 creator A5057125184 @default.
- W2793043164 date "2018-02-01" @default.
- W2793043164 modified "2023-09-30" @default.
- W2793043164 title "Dynamics Based Drug Design for Intrinsically Disordered Proteins" @default.
- W2793043164 doi "https://doi.org/10.1016/j.bpj.2017.11.3225" @default.
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