DNDI-6174, a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1 complex – Figures 3 and S2-8 raw data

New drugs for visceral leishmaniasis that are safe, low cost and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities with novel mechanisms of action that are suitable for clinical development remains low. Here, we describe the development of DNDI-6174, an inhibitor of Leishmania cytochrome b that originated from a phenotypically-identified pyrrolopyrimidine series. This compound fulfills all Target Candidate Profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with potential for sterile cure. No significant flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 represents the first cytochrome b inhibi..., Molecular modelling
Ligand and enzyme preparation: The 3D model of DNDI-6174 was created using LigPrep (Schrödinger Release 2021-2, LigPrep, Schrödinger, LLC, New York, NY, 2021), generating the most probable ionization state and tautomers at neutral pH (7.4 ± 0.2). Our previously reported homology model of L. donovani cytochrome b (8) was processed using the protein preparation module in the Schrödinger suite to provide starting points for subsequent molecular modelling studies. New structures were generated incorporating each of the five mutations found to drive drug resistance. For every mutant, the hydrogen atoms’ positions were optimized using the H-bond assignment/sample water orientation tool, and the resulting structures were subjected to a restrained minimisation procedure with the OPLS3e force field. This was achieved using the minimisation protocol of the protein preparation module of the Schrödinger’s suite of software.
Molecular docking: Molecular docking was performed usin..., , # DNDI-6174, a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1 complex - Figures 3 and S2-8 raw data

[https://doi.org/10.5061/dryad.44j0zpcm8](https://doi.org/10.5061/dryad.44j0zpcm8)

## Description of the data and file structure

For Fig 3, the model structure of DNDI-6174 bound in the Qi site of L. donovani cytochrome b is available as PDB file
For Fig 2S, the model structures of the mutated versions of cytochrome b are available as PDB files
For Fig S3-S8, the .aef files associated to the analysis of the MD trajectories are provided