Small molecule drug discovery suite 2018 4

Docking of Debio-1452 derivatives into FabI crystal structures was performed with the Small-Molecule Drug Discovery Suite 2018-4 (Schrodinger, New York, NY). Co-crystal structures of Debio-1452 bound to E. coli FabI (PDB: 4JQC) and S. aureus FabI (PDB: 4FS3) were prepared using the Protein Prep Wizard with default settings and used to build receptor grids. For S. aureus FabI allowed rotation for Tyr157 and NADP hydroxyls. For E. coli FabI allowed rotation for Tyr156 and NAD hydroxyls. Positional constraints were applied on the benzofuran ring (center of mass must be within 2 Å of initial position). H-bonding constraints were applied to Tyr156 and Ala95 (E. coli numbering). Ligands were prepared with LigPrep and amines were protonated. Both enantiomers of each ligands were docked with Glide XP. The poses of higher scoring enantiomers were refined and ΔΔG_bind was calculated using Prime MM-GBSA. Protein residues within 5 Å of the ligand were sampled using the hierarchical sampling procedure in Prime MM-GBSA.

The computational modeling experiments were conducted using the Schrödinger Small-Molecule Drug Discovery Suite (2018-4) as previously described.^{7 (link)} Briefly, the crystal structure 5EZY was downloaded from PDB and optimized using the Protein Preparation Wizard. The optimized protein structure was simplified by only retaining chain B comprising the taccalonolide AJ-β-tubulin complex. All water molecules were removed except for that forming H-bonds between β-tubulin Thr223 and the C-26 carbonyl group of taccalonolide AJ. The ligand structures were optimized using the Ligand Preparation Wizard (LigPrep). Further covalent docking experiments were performed using CovDock with Asp226 selected as the reactive residue. The docking box was centered on the coordinates X 3.2 / Y −63.5 / Z 22.6 in the length of 20 Å. The top 10 low-energy poses were generated and retained for each docking experiment. The lowest-energy pose showing the correct spatial arrangement of the taccalonolide core structure was selected for analysis of the ligand-protein binding modes.