10.1021/acs.jcim.5b00278.s001
Hervé Hogues
Hervé
Hogues
Traian Sulea
Traian
Sulea
Enrico O. Purisima
Enrico O.
Purisima
Evaluation of the Wilma-SIE Virtual Screening Method
in Community Structure–Activity Resource 2013 and 2014 Blind
Challenges
American Chemical Society
2015
Diverse targets
congeneric ligands
ligand docking
nucleotide methyltransferase
tyrosine kinase
CSAR
serine protease
protonation states
decoy conformations
Good separation
Pose selection
Syk system
0.6. Poor affinity
affinity predictions
platform
solvation model
FiSH model
solvated interaction energy
challenges validates
2014 editions
SIE function
crystal structures
Resource
target structures
1 Å
SAMPL
2015-08-17 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Evaluation_of_the_Wilma_SIE_Virtual_Screening_Method_in_Community_Structure_Activity_Resource_2013_and_2014_Blind_Challenges/2140471
Prospective
assessments of the Wilma-SIE (solvated interaction
energy) platform for ligand docking and ranking were performed during
the 2013 and 2014 editions of the Community Structure–Activity
Resource (CSAR) blind challenge. Diverse targets like a steroid-binding
protein, a serine protease (factor Xa), a tyrosine kinase (Syk), and
a nucleotide methyltransferase (TrmD) were included. Pose selection
was achieved with high precision; in all 24 tests Wilma-SIE top-ranked
the native pose among carefully generated sets of decoy conformations.
Good separation for the native pose was also observed indicating robustness
in pose scoring. Cross-docking was also accomplished with high accuracy
for the various systems, with ligand median-RMSD values around 1 Å
from the crystal structures. Larger deviations were occasionally obtained
due to the rigid-target approach even if multiple target structures
were used. Affinity ranking of congeneric ligands after cross-docking
was reasonable for three of the four systems, with Spearman ranking
coefficients around 0.6. Poor affinity ranking for FXa is possibly
due to missing structural domains, which are present during measurements.
Assignment of protonation states is critical for affinity scoring
with the SIE function, as shown here for the Syk system. Including
the FiSH model improved cross-docking but worsened affinity predictions,
pointing to the need for further fine-tuning of this newer solvation
model. The consistently strong performance of the Wilma-SIE platform
in recent CSAR and SAMPL blind challenges validates its applicability
for virtual screening on a broad range of molecular targets.