Use of Solvent Mapping for Characterizing the Binding Site and for Predicting the Inhibition of the Human Ether-á-Go-Go-Related K Channel.

Molecular dynamics was used to optimize the droperidol-hERG complex obtained from docking. To accommodate the inhibitor, residues T623, S624, V625, G648, Y652, and F656 did not move significantly during the simulation, while F627 moved significantly. Binding sites in cryo-EM structures and in structures obtained from molecular dynamics simulations were characterized using solvent mapping and Atlas ligands, which were negative images of the binding site, were generated.

The influence of calculated physicochemical properties of compounds on their ADMET profiles.

We analyzed the influence of calculated physicochemical properties of more than 20,000 compounds on their P-gp and BCRP mediated efflux, microsomal stability, hERG inhibition, and plasma protein binding. Our goal was to provide guidance for designing compounds with desired pharmacokinetic profiles. Our analysis showed that compounds with ClogP less than 3 and molecular weight less than 400 will have high microsomal stability and low plasma protein binding.

The statistics of virtual screening and lead optimization.

Analytic formulae are used to estimate the error for two virtual screening metrics, enrichment factor and area under the ROC curve. These analytic error estimates are then compared to bootstrapping error estimates, and shown to have excellent agreement with respect to area under the ROC curve and good agreement with respect to enrichment factor. The major advantage of the analytic formulae is that they are trivial to calculate and depend only on the number of actives and inactives and the measured value of the metric, information commonly reported in papers.

FRED and HYBRID docking performance on standardized datasets.

The docking performance of the FRED and HYBRID programs are evaluated on two standardized datasets from the Docking and Scoring Symposium of the ACS Spring 2011 national meeting. The evaluation includes cognate docking and virtual screening performance. FRED docks 70 % of the structures to within 2 Å in the cognate docking test.

FRED pose prediction and virtual screening accuracy.

Results of a previous docking study are reanalyzed and extended to include results from the docking program FRED and a detailed statistical analysis of both structure reproduction and virtual screening results. FRED is run both in a traditional docking mode and in a hybrid mode that makes use of the structure of a bound ligand in addition to the protein structure to screen molecules. This analysis shows that most docking programs are effective overall but highly inconsistent, tending to do well on one system and poorly on the next.

Gaussian docking functions.

A shape-based Gaussian docking function is constructed which uses Gaussian functions to represent the shapes of individual atoms. A set of 20 trypsin ligand-protein complexes are drawn from the Protein Data Bank (PDB), the ligands are separated from the proteins, and then are docked back into the active sites using numerical optimization of this function. It is found that by employing this docking function, quasi-Newton optimization is capable of moving ligands great distances [on average 7 A root mean square distance (RMSD)] to locate the correctly docked structure.