130 | wileyonlinelibrary.com/journal/cbdd Chem Biol Drug Des. 2020;95:130–149. © 2019 John Wiley & Sons A/S. 1 | INTRODUCTION Parasitic diseases continue to be a health problem at a global scale due to the acquisition of resistance by parasites, the rapid transmission by migration, and climatic change (Hotez, 2018). Although the progress toward their control or elim- ination has improved, the search for new targets that affect important life processes in parasites and compromise their survival will always be necessary as part of the arms race be- tween parasites and humans. In this sense, gene transcription is an essential process for survival of all living beings and therefore an attractive target. In eukaryotes, the transcription basal machinery is widely conserved among different spe- cies (Duttke, 2015; Sainsbury, Bernecky, & Cramer, 2015). A central basal transcription factor is the TATA‐binding protein (TBP), which is also present in archaea (Rowlands, Baumann, & Jackson, 1994). TBP recognizes the TATA box and promotes the recruitment of the transcription pre‐initi- ation complex by the three nuclear RNA polymerases. The TBP DNA‐binding domain structure is conserved across spe- cies (Figure 1a), with a length of about 180 amino acid res- idues (Adachi et al., 2004; Adachi, Senda, Natsume, Senda, & Horikoshi, 2008). Structures for this domain have been solved by nuclear magnetic resonance or X‐ray crystallog- raphy for the TBPs of Saccharomyces cerevisiae (Chasman, Flaherty, Sharp, & Kornberg, 1993), Arabidopsis thaliana (Nikolov & Burley, 1994), Homo sapiens (Bleichenbacher, Tan, & Richmond, 2003), Encephalitozoon cuniculi (Wollmann et al., 2011), Pyrococcus woesei (DeDecker et al., Received: 7 June 2019 | Revised: 14 August 2019 | Accepted: 21 September 2019 DOI: 10.1111/cbdd.13630 RESEARCH ARTICLE The TATA‐binding Protein DNA‐binding domain of eukaryotic parasites is a potentially druggable target Ángel Santiago 1,2 | Rodrigo Said Razo‐Hernández 1 | Nina Pastor 1 1 Centro de Investigación en Dinámica Celular ‐ IICBA, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México 2 Doctorado en Ciencias, CIDC‐ IICBA, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México Correspondence Nina Pastor, Centro de Investigación en Dinámica Celular ‐ IICBA, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, Chamilpa, 62209 Cuernavaca, Morelos, México. Email: nina@uaem.mx Abstract 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 struc- tural 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 dynam- ics simulations and to evaluate their druggability by molecular ensemble‐based dock- ing 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 docking, druggable target, molecular dynamics, TATA‐binding protein