Torrey Pines Institute for Molecular Studies

About: Torrey Pines Institute for Molecular Studies is a nonprofit organization based out in San Diego, California, United States. It is known for research contribution in the topics: T cell & Antigen. The organization has 2323 authors who have published 2217 publications receiving 112618 citations.

Improving CAPRI predictions: Optimized desolvation for rigid-body docking

Abstract: The ICM Docking and Interface Side-Chain Optimization (ICM-DISCO) showed promising predictive results during the first CAPRI experiment by successfully finding medium- or high-accuracy models in 3 of the 7 targets. A key factor was the ability to recognize near-native rigid-body geometries in a relatively low number of alternative docking poses, together with the successful refinement of the rigid-body docking interfaces. Since then, we have focused on improving the scoring function to optimally discriminate the near-native rigid-body conformations. For that, we have defined a new desolvation descriptor for rigid-body docking, based on atomic solvation parameters (ASPs) derived from octanol-water transfer experiments. This and other new approaches have been gradually incorporated into our docking procedure during our participation on the second CAPRI experiment. Overall, we produced reasonable models for 8 of the 9 official targets. Especially encouraging were those cases in which a homology model of 1 of the subunits had to be used during the docking simulations. And not less gratifying has been the successful prediction of antibody-antigen targets in a completely automatic, unrestrained fashion. In summary, our success rate (89%) shows a consistent improvement over the previous CAPRI rounds, and suggests that a correct desolvation description is key for improved protein-protein docking predictions.

Fructose-1,6-bisphosphatase Inhibitors. 1. Purine Phosphonic Acids as Novel AMP Mimics

Abstract: Inhibition of FBPase is considered a promising way to reduce hepatic gluconeogenesis and therefore could be a potential approach to treat type 2 diabetes Herein we report the discovery of a series of purine phosphonic acids as AMP mimics targeting the AMP site of FBPase, which was achieved using a structure-guided drug design approach These non-nucleotide purine analogues inhibit FBPase in a similar manner and with similar potency as AMP More importantly, several purine analogues exhibited potent cellular and in vivo glucose-lowering activities, thus achieving proof-of-concept for inhibiting FBPase as a drug discovery target For example, compounds 411 and 413 are as equipotent as AMP with regard to FBPase inhibition Furthermore, compound 411 inhibited glucose production in primary rat hepatocytes and significantly lowered blood glucose levels in fasted rats