Abstract
Intrinsically disordered proteins exist as highly dynamic conformational ensembles of diverse forms. However, the majority of virtual screening only focuses on proteins with defined structures. This means that computer-aided drug discovery is restricted. As a breakthrough, understanding the structural characteristics of intrinsically disordered proteins and its application can open the gate for unrestricted drug discovery. First, we segmented the target disorder-to-order transition region into a series of overlapping 20-amino-acid-long peptides. Folding prediction generated diverse conformations of these peptides. Next, we applied molecular docking, new evaluation score function, and statistical analysis. This approach successfully distinguished known compounds and their corresponding binding regions. Especially, Myc proto-oncogene protein (MYC) inhibitor 10058F4 was well distinguished from others of the chemical compound library. We also studied differences between the two Methyl-CpG-binding domain protein 2 (MBD2) inhibitors (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))). Both compounds bind MBD2 through electrostatic interaction behind its p66α-binding site. ABA is also able to bind p66α through electrostatic interaction behind its MBD2-binding site while APC-p66α binding was nonspecific. Therefore, structural heterogeneity mimicking of the disorder-to-order transition region at the peptide level and utilization of the new docking score function represent a useful approach that can efficiently discriminate compounds for expanded virtual screening toward intrinsically disordered proteins.
Highlights
Computer-aided drug discovery represents a usual initiation of the drug development pathway
We used a modified rational drug design approach for the discovery of drug leads based on molecular docking and molecular dynamics (MD) simulations of the intrinsically disordered protein regions (IDPRs) of target proteins capable of the disorder-to-order transitions (DOTs) [12]
The process started with the analysis of the intrinsic disorder predisposition of a drug target protein of interest followed by the prediction of the presence of potential disorder-based binding regions that can undergo DOTs
Summary
Computer-aided drug discovery represents a usual initiation of the drug development pathway. Virtual screening depends on the knowledge of the structure of target proteins determined by X-ray crystallography, solution or solid-state NMR (Nuclear Magnetic Resonance), cryo-EM (Electron Microscopy), and sometimes homology modeling. This means that virtual screening is limited to the set of proteins with known structures, disease does not always occur due to some problems pertaining to the ordered proteins. Blocking such proteins is not always a perfect solution [2,3]. The major field of current computer-aided drug discovery process, virtual screening, is restricted to searches within a very limited space at the bottom of the funnel
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