PL-PatchSurfer: A Novel Molecular Local Surface-Based Method for Exploring Protein-Ligand Interactions

Structure-based computational methods have been widely used in exploring protein-ligand interactions, including predicting the binding ligands of a given protein based on their structural complementarity. Compared to other protein and ligand representations, the advantages of a surface representation include reduced sensitivity to subtle changes in the pocket and ligand conformation and fast search speed. Here we developed a novel method named PL-PatchSurfer (Protein-Ligand PatchSurfer). PL-PatchSurfer represents the protein binding pocket and the ligand molecular surface as a combination of segmented surface patches. Each patch is characterized by its geometrical shape and the electrostatic potential, which are represented using the 3D Zernike descriptor (3DZD). We first tested PL-PatchSurfer on binding ligand prediction and found it outperformed the pocket-similarity based ligand prediction program. We then optimized the search algorithm of PL-PatchSurfer using the PDBbind dataset. Finally, we explored the utility of applying PL-PatchSurfer to a larger and more diverse dataset and showed that PL-PatchSurfer was able to provide a high early enrichment for most of the targets. To the best of our knowledge, PL-PatchSurfer is the first surface patch-based method that treats ligand complementarity at protein binding sites. We believe that using a surface patch approach to better understand protein-ligand interactions has the potential to significantly enhance the design of new ligands for a wide array of drug-targets

Synthesis and Pharmacological Characterization of 4‑Substituted-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: Identification of New Potent and Selective Metabotropic Glutamate 2/3 Receptor Agonists

As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1<i>S</i>,2<i>S</i>,5<i>R</i>,6<i>S</i>-2-aminobicyclo­[3.1.0]­hexane-2,6-dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation of relatively small substituents (e.g., F, O) at the C4 position of this molecule resulted in additional highly potent mGlu2/3 agonists that demonstrate excellent selectivity over the other mGlu receptor subtypes, while addition of larger C4-substituents (e.g., SPh) led to a loss of agonist potency and/or the appearance of weak mGlu2/3 receptor antagonist activity. Further characterization of the α-fluoro-substituted analogue (LY459477) in vivo revealed that this molecule possesses good oral bioavailability in rats and effectively suppresses phencyclidine-evoked locomotor activity at doses that do not impair neuromuscular coordination. This molecule therefore represents a valuable new addition to the arsenal of pharmacological tools competent to investigate mGlu2/3 receptor function both in vitro and in vivo

Synthesis and Pharmacological Characterization of <i>C</i>4‑(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1<i>R</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>R</i>)‑2-Amino-4-(1<i>H</i>‑1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu₂ Receptor Agonist

Identification of orthosteric mGlu_2/3 receptor agonists capable of discriminating between individual mGlu₂ and mGlu₃ subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1<i>S</i>,2<i>S</i>,5<i>R</i>,6<i>S</i>)-2-aminobicyclo­[3.1.0]­hexane-2,6-dicarboxylate <b>1</b> (LY354740) bearing <i>C</i>4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu_2/3 subtypes, a number of high potency and efficacy mGlu₂ receptor agonists exhibiting low potency mGlu₃ partial agonist/antagonist activity were identified. From this, (1<i>R</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>R</i>)-2-amino-4-(1<i>H</i>-1,2,4-triazol-3-ylsulfanyl)­bicyclo­[3.1.0]­hexane-2,6-dicarboxylic acid <b>14a</b> (LY2812223) was further characterized. Cocrystallization of <b>14a</b> with the amino terminal domains of hmGlu₂ and hmGlu₃ combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of <b>14a</b> in a rat model responsive to mGlu₂ receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu₂ receptors in vivo