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All seven compounds exhibited good activity Table 1 and Supplementary Fig. The binding strength of these seven compounds was measured further using surface plasmon resonance SPR. After a c-terminal biotinylated c-Myc — peptide was immobilized onto a SA chip, serial concentrations of compounds were injected. The binding signals were continuously recorded in response units RU and presented graphically as a function of time.

As shown in Fig.

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S2 , all seven compounds bound biotinylated c-Myc — in a concentration-dependent manner. Overexpression of the c-Myc gene in the human promyelocytic leukaemia cell line HL is pivotal in carcinogenesis. The MTT assay has been used to test the inhibitory activity of F4 and other compounds on HL cell growth 24 , 35 , 36 , 37 , 38 , 39 , 40 , We also used this assay to examine whether these seven compounds abrogate cell proliferation.

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Our results demonstrate that HL cells were sensitive to four of the seven compounds in a dose-dependent manner Fig. S3 , and Table 1. The EC 50 was We further examined whether the reduced cell numbers observed in the MTT assay were caused by cytotoxicity or by an effect on cell cycle progression. S4 , and Table 1.


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Chemical cross-linking and anti-Max western blotting results are shown left. Blackness integrals of the GST-Max homodimer percentage are shown as a histogram right.

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The differences in the spectrum derived after subtracting the reference spectrum in which the large molecule 1 H are not irradiated, and hence no magnetization transfer occurs, identifies which of the 1 H of the small molecule are in closest contact with the large molecule in the bound state 42 , Selective irradiation was placed at approximately 0. The initial complex structures were built by molecular docking and then five independent nanosecond simulations were performed.

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Even though the compounds were residing in their binding sites in the initial structures, they could hover along the c-Myc — structure during the simulation course Fig. S8 , respectively. By using a structure-based virtual screen approach, we successfully discovered seven molecules that bind directly to the c-Myc disordered bHLH-LZ domain and inhibit c-Myc-Max dimerization. Four compounds exhibited micromolar binding affinity and inhibited cancer cell growth.

None of the compounds appeared to match the list of PAINS compounds, therefore, they may not be promiscuous None of these compounds were reported previously to inhibit c-Myc activity. To the best of our knowledge, this is the first successful example that used a structure-based design approach to discover compounds that directly bind to the c-Myc conformation ensemble and inhibit its biological function.

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Only a few compounds that inhibit c-Myc-Max dimerization have been reported in the last decade. In , Berg et al. In , Yin et al. Compared to the high-throughput screening approaches used previously, our strategy directly targets the disordered bHLH-LZ domain of c-Myc, which is more efficient. Experimental testing of the compounds predicted by the computational screen identified seven active ones.

Another question that arises from directly targeting IDPs with small molecules is whether the binding is truly specific. Additionally, the flexibility of the disordered region makes it possible for an IDP to bind a diversity of conformations of one compound with similar affinities. All four compounds formed hydrogen bonds with the backbone oxygen atom from Glu through the two hydrogen atoms of the thiourea group.

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They also formed a hydrogen bond with the backbone oxygen atom from Asp via the hydrogen from the acylamino group in the docking mode Supplementary Fig. Further optimization of these compounds can be performed based on this analysis. To test whether computer-aided drug design targeting an intrinsically disordered region is feasible, we performed a virtual screen for compounds that can bind to free and bound conformations of c-Myc — Therefore, based on our study, we propose a general approach for directly targeting IDPs.

First, comprehensive conformation sampling should be performed for the IDPs and some representative or lower energy conformations should be selected for virtual screening. Finally, various experimental methods can be used to validate activity. In conclusion, we have used a general approach for structure-based discovery of IDP binding molecules to discover compounds that bind to the c-Myc disordered bHLH-LZ domain and prevent c-Myc-Max dimerization. Seven compounds were successfully discovered and four of them were active in cell-based assays.

Because many IDPs are related to human diseases, this approach provides a useful tool to make them truly druggable. We used CAVITY, a program for binding site detection and druggability assessment, to predict potential binding sites in c-Myc — Two sites in the Apo conformation and one in the Holo conformation were identified: cavity Apo1 in c-Myc — , Apo2 in c-Myc — , and Holo1 in c-Myc — Molecular docking studies were performed using Glide 32 , Analogue screening of A4 was conducted using Phase The compounds were added from stock solutions in ethanol.

For each CD experiment, the corresponding concentration of compound was used as the blank. The apparent K d was calculated using the Hill equation. The data obtained was analysed with the Biacore T Evaluation Software 2. The K d values were obtained from steady state fitting of the response-concentration plot to the equilibrium curves.

Cells in the exponential growth phase were used for experiments. Results were expressed as a percentage of inhibition and the EC 50 was calculated using the Hill equation. The compounds were added from stock solutions in DMSO resulting in a final concentration of 0.

Negative control reactions lacking cDNA template were included to assess specificity, and showed no appreciable amplification. The fluorescence intensity is related to the initial number of RNA copies, which can be assessed by determining the threshold cycle C T. These samples were treated in duplicate. Next, the blots were probed with horseradish peroxidase-conjugated goat anti-rabbit IgG antibody Santa Cruz Biotechnology Inc.

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Samples containing 0. TOCSY spectra were acquired with a relaxation delay of 1. The number of scans was and the spectral width was 16 ppm. The initial complex structures were built by molecular docking using the Glide 32 , 33 software in SP mode. The system was minimized using the steepest descent and conjugate gradient minimization approaches. The systems were run with constant pressure and temperature NPT ensemble mode with periodic boundary conditions. For each complex, five ns simulations were performed. Amber Tools was used to analyse the simulation trajectories.

How to cite this article : Yu, C. Wright, P. Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. Dunker, A. The unfoldomics decade: an update on intrinsically disordered proteins. BMC Genomics 9 , S1 Uversky, V. Intrinsically disordered proteins from A to Z.

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Schlessinger, A. Protein disorder—a breakthrough invention of evolution? Huang, Y. Dyson, H. Intrinsically unstructured proteins and their functions. Ferreon, A. Modulation of allostery by protein intrinsic disorder. Nature , — Liu, Z. Advantages of proteins being disordered. Protein Sci. Metallo, S. Intrinsically disordered proteins are potential drug targets.

Cheng, Y.