Modelling data for: Short-course combination treatment for experimental chronic Chagas disease

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects millions of people in the Americas and across the world leading to considerable morbidity and mortality. Current treatment options, benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects due to long treatment durations. Better treatment options are therefore urgently required. Here we describe a pyrrolopyrimidine series, identified through phenotypic screening, that offers a clear opportunity to improve on current treatments. In vitro cell-based washout assays demonstrate that compounds in the series are incapable of killing all parasites, however, combining these pyrrolopyrimidines with a sub-efficacious dose of BNZ can clear all parasites in vitro after five days. Importantly, these findings were replicated in a clinically predictive in vivo model of chronic Chagas disease, where five days of treatment with the combination was sufficient to prevent parasite relapse. Co..., Protein and ligand preparation for molecular modelling
Our molecular modelling studies were based on a previously generated homology model of T. cruzi cytochrome b. The protein structure with a conserved water molecule interacting with F33 was prepared using the Protein Preparation module in the Schrödinger suite (Schrödinger Release 2021-2). Protonation states were assigned by PROPKA at pH 7.0, and the hydrogen bonding network was consequently optimized. A restrained energy minimization step was then executed using the OPLS4 force field with default settings. Models of cytochrome b bearing either L197I or F222L mutations were prepared in Maestro by mutating one residue at a time. Subsequently, the mutated versions of cytochrome b were processed with the Protein Preparation tool in an identical manner to the wild-type enzyme.
Ligand structures (compounds 1-4) were prepared with Schrödinger’s LigPrep (Schrödinger Release 2021-2). All possible tautomeric forms and stereoisomers were gener..., , **Modelling data for Short-course combination treatment for experimental chronic Chagas disease.**

https://doi.org/10.5061/dryad.95x69p8r7

The dataset contains PDB files and molecular dynamics files for the modelling section of our manuscript.

Description of the data and file structure

Datafiles are provided for Figure 5, and Supplemental Information Figures S10, S11, S12, S13, S14, S15, S16 and S17.

Figure 5: Docking poses for compounds 1 – 4 into a homology model of T. cruzi cytochrome b.

Files:

Fig5A.pdb: PDB file for docking pose of compound 1 (5-(2-methoxyphenyl)-4,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine)

Fig5B.pdb: PDB file for docking pose of compound 3 (5-(4-Chloro-2-methoxyphenyl)-4,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine)

Fig5C.pdb: PDB file for docking pose of compound 2 (5-(4-Fluoro-2-methoxyphenyl)-4,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

Fig5D.pdb: PDB file for docking pose of compound 4 (5-(2,4-Dimethoxyphenyl)-4,6-dimethyl-7H-pyrrolo[2...