I have noticed that rigid docking methods, even when run with high-precision force fields, don’t always capture the correct poses for your true positives. Sometimes a hit will be docked somewhere other than into the site that you specified because the algorithm could not fit the molecule into the rigid receptor. This will cause true positives to be buried at the bottom of your ranked list.
You may want to try introducing receptor flexibility to improve the poses of your true positives. There are two main ways to do this: scale down the Van der Waals interactions to mimic flexibility (i.e., make the receptor atoms “squishy”) or use induced-fit docking (IFD) methods. I have found that while setting a lower threshold for VdW scaling can rescue false negatives (poorly docked true binders), at least in one case, it does not improve the overall ranking of all of the true positives. So it is not a panacea.
Induced fit methods work by mutating away several side chains in the binding pocket, docking a compound, mutating the side chains back, and energy minimizing the structure. Then the compound is re-docked to the minimized structure using a high-precision algorithm. There are two main applications for IFD: (1) improving the pose of a true positive that cannot be docked correctly by rigid docking and (2) rescuing false negatives.
My experience has been that IFD improves the docking scores of true positives and false positives by about the same amount, so the value of running the method on an entire library remains unclear. However, there is much value in running IFD on a true hit where you are not sure the rigid pose is optimal. Often, the improvement in the shape complementarity and number of interactions will be dramatic.
Also, you can use the alternative receptor conformations generated by IFD to a true positive to rescreen your library with faster rigid docking methods. If you are screening on a prospective basis, this approach could help you identify other chemotypes that may bind well but are missed in a first pass rigid docking screen.