Exhaustive search and solvated interaction energy (SIE) for virtual screening and affinity prediction

Abstract

We carried out a prospective evaluation of the utility of the SIE (solvation interaction energy) scoring function for virtual screening and binding affinity prediction. Since experimental structures of the complexes were not provided, this was an exercise in virtual docking as well. We used our exhaustive docking program, Wilma, to provide high-quality poses that were rescored using SIE to provide binding affinity predictions. We also tested the combination of SIE with our latest solvation model, first shell of hydration (FiSH), which captures some of the discrete properties of water within a continuum model. We achieved good enrichment in virtual screening of fragments against trypsin, with an area under the curve of about 0.7 for the receiver operating characteristic curve. Moreover, the early enrichment performance was quite good with 50% of true actives recovered with a 15% false positive rate in a prospective calculation and with a 3% false positive rate in a retrospective application of SIE with FiSH. Binding affinity predictions for both trypsin and host-guest complexes were generally within 2 kcal/mol of the experimental values. However, the rank ordering of affinities differing by 2 kcal/mol or less was not well predicted. On the other hand, it was encouraging that the incorporation of a more sophisticated solvation model into SIE resulted in better discrimination of true binders from binders. This suggests that the inclusion of proper Physics in our models is a fruitful strategy for improving the reliability of our binding affinity predictions.

Small-Molecule Inhibitors of the Pseudaminic Acid Biosynthetic Pathway: Targeting Motility as a Key Bacterial Virulence Factor

“…In parallel with the HTS screening of an actual compound library, we took advantage of some of the structural information available for enzymes in the Pse biosynthetic pathway. We carried out VS of a virtual library of 1.6 million compounds against the crystal structures of PseB and PseG, using a proprietary VS pipeline that demonstrated some of the better performances in blind tests (32,33). We acquired 38 virtual hits from the PseG screening and 42 virtual hits from the PseB screening and tested them in the 5-enzyme assay described earlier.…”

“…We used a high-throughput VS docking-scoring pipeline (32,33). The exhaustive docking program Wilma (32) within the VS pipeline was used with default increment parameters and the WilmaScore1 energy function (34).…”

“…The ligand conformations were generated by Omega (OpenEye, Inc., Santa Fe, NM) and controlled by setting the internal energy cutoff to 20 kcal/mol and adjusting the pose clustering parameter to produce at most 5,000 conformations. Wilma-generated poses were refined by constrained energy minimization as described previously (32)(33)(34) prior to binding affinity scoring with the solvated interaction energy (SIE) function (35) using default parameters for the electrostatic and nonpolar contributions to interaction and desolvation energies (34,36). Pose selection for a given inhibitor against a given enzyme variant was based on the lowest SIE score.…”

Evaluation of the Wilma-SIE Virtual Screening Method in Community Structure–Activity Resource 2013 and 2014 Blind Challenges

“…To this end we developed Wilma, an exhaustive docking program that has the required efficiency for large-scale virtual screening of drug-like compound libraries. 4,5 Owing to its exhaustive nature as well as to its fast empirical pose-ranking function calibrated on crystal structures of protein−ligand complexes, the top-ranked pose produced by Wilma has been shown to be consistently close to the experimental pose for drug-like ligands. The second ingredient required in a virtual screening method is accurate scoring, so Wilma was coupled with the solvated interaction energy (SIE) scoring function.…”

Protein–Ligand Binding Free Energies from Exhaustive Docking

“…It was recently used successfully in SAMPL-3, a blind test for assessing algorithms for virtual screening and affinity prediction. 6 Torsional Sampling. Six of the eight ligands are essentially rigid, while isobutylbenzene and n-butylbenzene have two and three rotatable bonds, respectively.…”