Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2

Abstract

The intrinsically disordered region of MBD2 is a promising target for treating cancer metastasis.

Drug Discovery Targeting the Disorder-To-Order Transition Regions through the Conformational Diversity Mimicking and Statistical Analysis

“…Earlier, we discovered the anti-metastasis activities of two compounds, ABA and APC (see the Section 3 Materials and Methods) by targeting MBD2 in molecular docking environment [ 12 ]. In the field of rational drug design, it is a commonly accepted practice to apply molecular docking toward target protein structures determined by X-ray crystallography, NMR, and cryo-EM.…”

“…This analysis revealed that the MYC 402–412 region serves as the 10058F4 target site and is embedded within the MYC disorder-to-order transition region responsible for MAX binding [ 14 ]. Curiously, according to our previous study, in the MYC per-residue intrinsic disorder profile, this 402–412 segment corresponds to a region with a high positive slope [ 12 ].…”

“…However, the potential of this shift from ordered to disordered binding sites for the selection of promising drug targets was recently demonstrated by the traditional high-throughput screening-based discovery of the Myc proto-oncogene protein (MYC) inhibitors, including 10058F4 [ 10 , 11 ]. Furthermore, we recently elaborated an approach for the rational discovery of the inhibitors targeting such disorder-to-order transition regions and used this approach to find inhibitors targeting Methyl-CpG-binding domain protein 2 (MBD2) [ 12 ].…”

“…We also reported the discovery of two inhibitors targeting the disorder-to-order transition regions of MBD2 involved in an interaction with p66α [ 12 ]. We showed that the MBD2 segment that undergoes binding-induced disorder-to-order transition and forms coiled-coil dimer with its partner, p66α [ 15 ] (i.e., acts similarly to the MYC interacting with MAX [ 13 ]), is located within the region with a positive slope in the per-residue disorder profile of MBD2 [ 12 ]. By molecular docking utilized for virtual screening toward the coiled-coil disorder-to-order transition region of MBD2, we obtained two positive hits, ABA (2-amino-N-[[(3S)-2,3-dihydro-1,4-benzodioxin-3-yl]methyl]-acetamide) and APC (R)-(3-(2-Amino-acetylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester).…”

“…By molecular docking utilized for virtual screening toward the coiled-coil disorder-to-order transition region of MBD2, we obtained two positive hits, ABA (2-amino-N-[[(3S)-2,3-dihydro-1,4-benzodioxin-3-yl]methyl]-acetamide) and APC (R)-(3-(2-Amino-acetylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester). These compounds were shown to possess noticeable anti-metastasis activity due to the inhibition of the MBD2–p66α complex formation [ 12 ]. However, we did not analyze whether these two compounds can distinguish MBD2 and p66α (which has a disordered region that undergoes disorder-to-order transition while forming the coiled-coil heterodimer with MBD2).…”