GLIMPSED: An Improved Docking Protocol for Cognate Docking

The cognate docking performance of Glide was evaluated using the Astex diverse set. The standard Glide SP protocol obtained a 85.7 % success rate when the shape similarity cutoff was set to 0.625. The analysis of docking failures pointed out that, when the SiteMap binding site exposure is less than 0.491, 51 out of 52 ligands are correctly positioned. In light of this important finding, an improved docking protocol called GLIMPSED was set up. GLIMPSED relies on the standard Glide SP protocol for binding sites with low exposure, while a more accurate sampling of docking poses followed by a final MM-GBSA rescoring is performed for those highly exposed to the solvent. GLIMPSED and Glide SP were compared applying an accurate and rigorous metrics described in the literature by Hawkins et al. As a result, GLIMPSED was able to dock 89.3 % of the ligands in a correct way. Even though this number is not remarkably different from that obtained with the standard method, it is indeed statistically significant. Applying the Cohen's effect size test, a small, but not trivial, superiority of GLIMPSED was found with respect to standard Glide SP protocol. In our view the SiteMap binding site exposure parameter should be used as guideline to decide whether either a standard or a more extended docking protocol has to be adopted to predict good binding poses.