The TATA-binding protein (TBP) is a central transcription factor in eukaryotes that interacts with a large number of different transcription factors; thus, affecting these interactions will be lethal for any living being. In this work, we present the first structural and dynamic computational study of the surface properties of the TBP DNA-binding domain for a set of parasites involved in diseases of worldwide interest. The sequence and structural differences of these TBPs, as compared with human TBP, were proposed to select representative ensembles generated from molecular dynamics simulations and to evaluate their druggability by molecular ensemble-based docking of drug-like molecules. We found that potential druggable sites correspond to the NC2-binding site, N-terminal tail, H2 helix, and the interdomain region, with good selectivity for Plasmodium falciparum, Necator americanus, Entamoeba histolytica, Candida albicans, and Taenia solium TBPs. The best hit compounds share structural similarity among themselves and have predicted dissociation constants ranging from nM to μM. These can be proposed as initial scaffolds for experimental testing and further optimization. In light of the obtained results, we propose TBP as an attractive therapeutic target for treatment of parasitic diseases.
Keywords: TATA-binding protein; docking; druggable target; molecular dynamics.
© 2019 John Wiley & Sons A/S.