Sybyl

Small molecules were built in Sybyl (Certara Corp.) and saved in mol2 format. The two TPI protein receptors from Trypanosoma cruzi (PDB code 1tcd) and S. cerevisiae (1ypi) were prepared in Sybyl using the protein preparation tools to add hydrogens, properly type atoms, and remove any clashes. AutoDock Tools^{86 (link)} were used to prepare the ligand and receptor pdbqt files and to select the docking box size for Autodock4. The docking box size was large enough to include the dimer interface described by Kurkcuoglu et al.^{50 (link)}. Autodock4.2.6 was run with Lamarkian Genetic Algorithm, with 25 M energy evaluations for 27,000 generations. This method includes a Solis & Wets local search of the ligand in the receptor after docking. Autodock 4.2.6 calculates a binding energy by summation of the molecular energy components (vdw + Hbonding + desolvation + electrostatics + ligand torsional free energy) minus the unbound system energy. The 30 best-docked ligands were examined. Optimal docking results were displayed in Pymol (PyMOL Mol. Graphics System, Ver. 1.8.2, Schrodinger, LLC).

Docking of compound 50 was accomplished with the Surflex 2.7’s molecular docking
module (surflex-dock; Sybyl, Certara) and the PDB ID 6P3P, which is based
on conformation optimization procedures implemented for morphological
similarity, that fragments the molecule, docks the fragments, and
reconstructs the molecule in the active site of the protein. The ligand
in 6P3P was
used to define a binding region and as a test ligand for the docking
protocol. The binding pose predicted by the protocol closely resembled
the experimental docked geometry of the experimentally derived binding
pose for the ligand (not shown). Subsequently, the molecular model
of compound 50 was generated, energy minimized, and docked
using the same protocol. Molecular models were analyzed using MOE
2019.0101 (Chemical Computing Group) or Chimera (http://www.cgl.ucsf.edu/chimera).