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Recent breakthroughs in GPCR structural biology have significantly increased our understanding of drug action at these therapeutically relevant receptors, and this will undoubtedly lead to the design of better therapeutics. In recent years, crystal structures of GPCRs from classes A, B, C and F have been solved, unveiling a precise snapshot of ligand-receptor interactions. Furthermore, some receptors have been crystallized in different functional states in complex with antagonists, partial agonists, full agonists, biased agonists and allosteric modulators, providing further insight into the mechanisms of ligand-induced GPCR activation. It is now obvious that there is enormous diversity in the size, shape and position of the ligand binding pockets in GPCRs. In this review, we summarise the current state of solved GPCR structures, with a particular focus on ligand-receptor interactions in the binding pocket, and how this can contribute to the design of GPCR ligands with better affinity, subtype selectivity or efficacy.

The mole is a unit of measure. In baking, we say a dozen. In chemistry, we say a mole. Both simply describe a specific number of a quantity. For baking, a dozen is comprised of 12. For chemistry, a mole is comprised of 6.02 x 1023.

I found drugs that inhibit the main protease, Nsp12 and Nsp3. The discovered drugs are either in clinical trials (Sildenafil, Lopinavir, Ritonavir) or have in vitro antiviral activity (Nelfinavir, Indinavir, Amprenavir, depiqulinum , Gemcitabine, Raltitrexed, Aprepitant, montelukast, Ouabain, Raloxifene) whether against SARS CoV 2 or other viruses. In addition to this, further analysis of pockets revealed a steroidal pocket that might open the door to hypotheses on why the mortality of men is higher than women.

Many of the in silico repurposing studies test binding of the compound to the target using docking. The significance of this study adds to the similarity between the drug binding site and the target binding site. This takes into consideration the dynamic behaviour of the pocket after ligand binding.

H. pylori GR exists as an obligate dimer, with the active sites of each monomer facing one another (D-Glu is shown in the center of each monomer in blue and red). Structure PDB 2JFZ (brown ribbons) bound to Compound A (shown in green) bound to the allosteric pocket is superposed onto the inhibitor free form of the enzyme PDB 2JFX (yellow ribbons). Mechanistically, these structures alone are not sufficient to understand allosteric inhibition in this system, which is largely driveni by dynamics, as discussed in the text.

An important scientific and pharmaceutical question is whether or not structure based discovery approaches can be successfully applied to a cryptic allosteric pocket, as in the case of H. pylori GR, especially given our limited understanding of the manifold forms that such a pocket may take; it is particularly problematic due to the global flexibility of GR and a lack of experimental structural data about the apo form of the enzyme7. Although allosteric drugs hold enormous promise, the truth is that only 19 of more than 3700 FDA approved drugs are allosteric, and only a single drug was derived using approaches centering on in silico/structural methods20. These are extremely challenging problems, which necessitate the use of methods that stress test our computational and structural approaches. In this study we report an MD/Docking workflow which is stress tested via the Receiver Operator Characteristic (ROC) statistical method, and results in the successful discovery of a new allosteric inhibitor of H. pylori GR, but with a completely different chemical space than Compound A, proving that the workflow presented herein is able to address the challenges presented by cryptic allosteric pockets. Importantly, the MD-based discovery process itself reveals a distinct allosteric communication in the native system (no inhibitor) which occurs between monomers of the dimeric enzyme via a dynamic C-terminal -helix, which is dramatically dampened by complexation with the allosteric inhibitor. The dynamical data is strongly supported by the pattern in the crystallographic B-factors in the inhibited and uninhibited complexes of H. pylori GR, which has not been previously recognized. These findings constitute a definitive and novel type of Allosteric Structure Activity Relationship (ASAR).

In terms of the effects of these dynamics on active site catalytic chemistry, the orientation and distance of Cys181 from the -carboxylate oxygen of D-Glu is important for the for the pre-activation step (i.e., protonation of the C-carboxylate oxygen). Only after the proton transfer to the -carboxylate oxygen does the pKa of C- hydrogen reduce enough to facilitate its abstraction by Cys7015. During MD simulation of H. pylori GR inhibited by NP-020560, Cys181 rotates frequently between conformations facing towards and away from D-Glu (Fig. 6b), relative to the uninhibited simulation. More importantly, the distance between Cys181 and -carboxylate of D-Glu is considerably higher in the presence of NP-020560 as compared to uninhibited state of GR (Fig. 6c, d), hindering pre-activation chemistry. Overall, what we observe is that when NP-020560 is bound in the allosteric pocket, it alters the distance and orientation of Cys181 (part of the active site) and predisposes the enzyme to a conformation that is unfavorable to perform the racemization.

Based on the previous and current observations, it is clear that the pre-activation step (protonation of the C carboxylate) is key to the ability of GR to carryout stereo-inversion of D-Glu and is dependent on the highly flexible and dynamic nature of GR. Occupancy of the cryptic allosteric pocket by a small molecule dampens coupled motions between two monomers of GR (and this is the operative mechanism for Compound A as well). This reveals the existence of a deeper monomer-monomer interaction in GR in the uninhibited state, the inhibition of which is a novel means of allosteric control by a small molecule, and for the first time explains why GR enzymes in general are almost always found as active dimers. Indeed, this supports the possibility that H. pylori GR must be a viable dimer to have catalytic activity. This fundamental knowledge about how H. pylori GR is harnessing catalytic power via monomer-monomer cross-talk is a very unexpected and important result from this allosteric drug discovery campaign.

Helicobacter pylori glutamate racemase is an essential protein for microbial survival and is an attractive drug target. Due to its high inherit flexibility and poor druggability at the active site, application of classic structure-based design approaches has been challenging. These challenges were overcome by developing a hybrid molecular dynamics-based docking workflow, which targeted a cryptic allosteric pocket, taking into account both global dynamics in the enzyme as well as the fitness of the receptor for selecting true positives in in silico screening. The key steps in the protocol include an all-atom MD simulation on the starting protein to evaluate additional conformations followed by using a decoy library to challenge the workflow and identify the best performing receptor-docking pair for virtual screening. The power of the developed workflow was demonstrated by screening and identifying natural product inhibitors of H. pylori GR.

Two different docking programs where then used since each takes a different approach for ligand placement and for searching minimum energy confirmations: FlexX (part of LeadIT available from BioSolveIT GmbH)51,52 and MOE 201638. The 144-compound test library was docked into the cryptic allosteric pocket of each of the 16 protein structures (9 for 2JFZ and 7 for 4B1F) (Table 1).

Periodic table of the elements, equation balancer, molecular mass calculator - all this andmore can be found in Pocket Chemistry. It provides you with a set of tools for PocketPC PDA whichcan be useful in chemistry lessons, in labs, at home, etc. If you have anything to do withchemistry, this program is for you.

Many a great idea has come out of the ACS national meetings. For chemist John A. Pojman Sr., one of these inspirational moments came during the 2000 national meeting in San Francisco when he happened across a pocket protector at the ACS store.

An apomyoglobin biliverdin complex was reduced to a bilirubin apomyoglobin complex with retention of the helix chirality of the chromophore. Chelation of the mesobiliverdin-XIII apomyoglobin complex with zinc ions in aqueous solution yielded an enantiomer of the corresponding derivative. These two systems document the possibility of using the heme pocket of apomyoglobin to execute stereospecific reactions. The chiroptical properties of the two product systems are discussed.

Figure 4. Alignments between the co-crystal structure TAM (gray) and the TAM-analogs (blue) at their absolute positions in the binding pocket in hormone receptors for (A) TAM-Hydroxyl, (B) TAM-Amide, (C) TAM-Carboxyl, and (D) TAM-Sulfhydryl.

Human neuropeptide Y receptors (Y1R, Y2R, Y4R, and Y5R) belong to the superfamily of G protein-coupled receptors and play an important role in the regulation of food intake and energy metabolism. We identified and characterized the first selective Y4R allosteric antagonist (S)-VU0637120, an important step toward validating Y receptors as therapeutic targets for metabolic diseases. To obtain insight into the antagonistic mechanism of (S)-VU0637120, we conducted a variety of in vitro, ex vivo, and in silico studies. These studies revealed that (S)-VU0637120 selectively inhibits native Y4R function and binds in an allosteric site located below the binding pocket of the endogenous ligand pancreatic polypeptide in the core of the Y4R transmembrane domains. Taken together, our studies provide a first-of-its-kind tool for probing Y4R function and improve the general understanding of allosteric modulation, ultimately contributing to the rational development of allosteric modulators for peptide-activated G protein-coupled receptors (GPCRs). 006ab0faaa