Metadynamics as a Postprocessing Method for Virtual Screening with Application to the Pseudokinase Domain of JAK2

With standard scoring
methods, top-ranked compounds from virtual
screening by docking often turn out to be inactive. For this reason,
metadynamics, a method used to sample rare events, was studied to
further evaluate docking poses with the aim of reducing false positives.
Specifically, virtual screening was performed with Glide SP to seek
potential molecules to bind to the ATP site in the pseudokinase domain
of JAK2 kinase, and promising compounds were selected from the top-ranked
1000 based on visualization. Rescoring with Glide XP, GOLD, and MM/GBSA
was unable to differentiate well between active and inactive compounds.
Metadynamics was then used to gauge the relative binding affinity
from the required time or the potential of mean force needed to dissociate
the ligand from the bound complex. With consideration of previously
known binders of varying affinities, metadynamics was able to differentiate
between the most active compounds and inactive or weakly active ones,
and it could identify correctly most of the selected virtual screening
compounds as false positives. Thus, metadynamics has the potential
to be a viable postprocessing method for virtual screening, minimizing
the expense of buying or synthesizing inactive compounds.