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This study was designed to develop a novel platform for the discovery of drug leads based on molecular docking and MD simulations of the DOT-associated IDPRs of target proteins and, as a proof of concept, to identify candidate drugs, suppressing metastatic potentials of cancer cells in vitro and in vivo, by targeting an IDPR of MBD2 that undergoes a DOT upon association with its binding partner p66α for the integration of the Mi-2/NuRD CRC. These objectives were addressed by (i) analyzing intrinsic disorder predispositions of drug-target proteins and evaluating potential disorder-based binding regions (45), (ii) doing molecular docking with druggable compounds from the ZINC compound library to the potential drug-target sites, (iii) selecting two lead compounds based on the docking scores and off-target probabilities and experimental validation of target binding, (iv) evaluating the mode and efficiency of the compound binding via MD simulations, (v) assessing the identified leads for biological effects suppressing metastatic potentials of cancer cells, and (vi) verifying antimetastatic efficacy in a murine xenograft tumor model.

In animal studies, mice were randomly assigned to treatment and control groups. Numbers of tested mice were specified in each figure. Outliers were removed only if mice died at an early stage of the treatment according to the Hanyang University Institutional Animal Care and Use Committee (IACUC) dimension guideline. The primary end points were tumor size and cancer metastasis to lung. Mice were euthanized when moribund or at the end of the prespecified treatment period. All procedures were performed in accordance with institutional protocols approved by the IACUC of the Hanyang University. Pathology analysis was performed in a blinded fashion.

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