Glide accurately predicts GMII metal-ligand interactions
A recent study in Proteins presented a head-to-head evaluation of seven leading docking programs to assess their accuracy in predicting metal-ligand interactions.1 The receptor investigated was Golgi α-mannosidase II (GMII) – a promising anti-tumor therapy target – which is a zinc dependent glycosyl hydrolase, and correctly determining the key metal binding interactions is vital. Glide did remarkably well in this study – the metal–binding atoms in 91% of the compounds had RMSDs below 0.75 Å. Here is what the authors have to say about Glide:
“Overall, Glide provided the best docking results, with the most accurately predicted binding around the active site zinc atom. Further evaluation of Glide’s performance revealed its ability to extract active compounds from a benchmark library of decoys…
“…Glide outperformed the other docking programs… Unexpectedly, the prediction of the metal coordination geometry appeared to be best with Glide/GlideScore even compared to other programs that included a specific term for metal ligation and coordination geometries.”
Glide identifies selective Stat3 inhibitor with anti-tumor activity in successful virtual screening application
Stat proteins participate in the regulation of cell growth, survival, and differentiation, and an increase in expression of Stat3 has been linked to numerous tumor types, including human breast cancer. In the Proceedings of the National Academy of Sciences, Siddiquee et al. recently published their discovery of a possible new Stat3 anti-tumor lead using Glide virtual screening.2 Beginning with over 150,000 compounds from the National Cancer Institute’s chemical libraries, each chemical structure was docked into the phosphotyrosine peptide-binding site within the Src homology 2 domain (SH2) to obtain the best-scoring compounds, which ultimately led to the identification of the selective Stat3 inhibitor, S3I-201.
“[Glide] structure-based high-throughput virtual screening of the National Cancer Institute (NCI) chemical libraries identified the high-scoring compound NSC 74859 (resynthesized as a pure sample and named S3I-201), which selectively inhibits Stat3 DNA-binding activity in vitro,… induces growth inhibition and apoptosis of malignant cells… and induces human breast tumor regression in xenograft models.”
1. Englebienne, P.; Fiaux, H.; Kuntz, D.A.; Corbeil, C.R.; Gerber-Lemaire, S.; Rose, D.R.; Moitessier, N. “Evaluation of docking programs for predicting binding of Golgi alpha-mannosidase II inhibitors: A comparison with crystallography.” Proteins. 2007, 69, 160-176.
2. Siddiquee, K.; Zhang, S.; Guida, W.C.; Blaskovich, M.A.; Greedy, B.; Lawrence, H.R.; Yip, M.L.; Jove, R.; McLaughlin, M.M.; Lawrence, N.J.; Sebti, S.M.; Turkson J. “Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity.” Proc. Natl. Acad. Sci. 2007, 104, 7391-7396.