1146-1-3ice4-PosePredictionProtocol.txt

Name

D3R-GC4-Pose-BestScore-Phase-1a

Software

CACTVS Chemoinformatics Toolkit v3.433/Schrödinger Suite 2018-1/CORINA v3.60/UCSF Chimera v1.10.2/GOLD v5.2

System Preparation Parameters

Protonation state of ligands at pH 7.0 was considered.

System Preparation Method

The PDB structure 3K5C was prepared (hydrogens added) using the Hermes graphical interface of GOLD software. The three-dimensional structures of BACE ligands (MOL2 format) were built manually using the Schrödinger's Maestro interface, based on similarity with existing PDB ligands. Alternatively (but these results are not submitted in phase 1), the three-dimensional structures of BACE ligands were generated from SMILES using CORINA. Protonation state corresponding to a pH of 7.0 was generated using Schrödinger LigPrep. Binding site was defined as a sphere with 20 Å radius around the atom OG of THR72.

Pose Prediction Parameters

Gold software with GoldScore scoring function
Search efficiency 200% # more adapted for flexible ligands
50 poses generated for each ligand

Pose Prediction Method

Preliminary calculations using Gold (with GoldScore, ChemScore, ChemPLP and ASP scoring functions), Glide (with SP parameters) and Vina and the BACE1 protein-ligand complexes available in PDB showed that best results in terms of pose prediction are obtained with Gold and GoldScore. Therefore, docking runs were executed using Gold and goldscore scoring function, and default values except search efficiency which was set to 200%. To explore ring conformations and the ligand flexibility the options flip ring corners, flip pyramidal N and flip amide bonds were activated. All the ligands were docked onto the 3K5C structure. The docking calculation was carried out with two hydrogen bond constraints involving the backbone oxygen atoms of residues GLY230 and GLY34 and any atoms of the ligands. Additional docking calculations were also carried out with ligands generated from SMILES, and also without any constraints. In all these cases, as expected, the poses are slightly worse compared to those obtained with constraints, and only the latter were submitted. All results will be discussed in detail in the D3R-GC4 paper.
The poses with the best docking score were selected for submission (1 pose per compound). Protein structures were converted into PDB format for submission using UCSF Chimera, and the docking poses were converted into MOL format using CORINA (the MOL format corresponds to the SDF output format in CORINA).

Answer 1

No

Answer 2

Yes