The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via Gq proteins to phospholipase C-β. The high-affinity receptor state requires both Mg2+ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has bee...

The Oxytocin Receptor System: Structure, Function, and Regulation

Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein-coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120.

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Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists.

Quantitative structure-activity and structureproperty relationship (QSAR/QSPR) studies are unquestionably of great importance in modern chemistry and biochemistry. The concept of QSAR/QSPR is to transform searches for compounds with desired properties using chemical intuition and experience into a mathematically quantified and computerized form. Once a correlation between structure and activity/property is found, any number of compounds, including those not yet synthesized, can be readily screened on the computer in order to select structures with the properties desired. It is then possible to select the most promising compounds to synthesize and test in the laboratory. Thus, the QSAR/QSPR approach conserves resources and accelerates the process of development of new molecules for use as drugs, materials, additives, or for any other purpose. While it is not easy to find successful structureactivity/property correlations, the recent exponential growth in the number of papers dealing with QSAR/ QSPR studies clearly demonstrates the rapid progress in this area. To obtain a significant correlation, it is crucial that appropriate descriptors be employed, whether they are theoretical, empirical, or derived from readily available experimental characteristics of the structures. Many descriptors reflect simple molecular properties and thus can provide insight into the physicochemical nature of the activity/ property under consideration. Recent progress in computational hardware and the development of efficient algorithms has assisted the routine development of molecular quantummechanical calculations. New semiempirical methods supply realistic quantum-chemical molecular quantities in a relatively short computational time frame. Quantum chemical calculations are thus an attractive source of new molecular descriptors, which can, in principle, express all of the electronic and geometric properties of molecules and their interactions. Indeed, many recent QSAR/QSPR studies have employed quantum chemical descriptors alone or in combination with conventional descriptors. Quantum chemistry provides a more accurate and detailed description of electronic effects than empirical methods.1 Quantum chemical methods can be applied to quantitative structure-activity relationships by direct derivation of electronic descriptors from the molecular wave function. In many cases it has been established that errors due to the approximate nature of quantum-chemical methods and the neglect of the solvation effects are largely transferable within structurally related series; thus, relative values of calculated descriptors can be meaningful even though their absolute values are not directly applicable.2 Moreover, electronic descriptors derived from the molecular wave function can be also partitioned on the basis of atoms or groups, allowing the description of various molecular regions separately. Most work employing quantum chemical descriptors has been carried out in the field of QSAR rather than QSPR, i.e. the descriptors have been correlated with biological activities such as enzyme inhibition activity, hallucinogenic activity, etc.3-6 In part this has been because, historically, the search for quantitative relationships with chemical structure started with the development of theoretical drug design methods. Quantum-chemical descriptors have also been reported to correlate the reactivity of organic compounds, octanol/water partition coefficients, chromatographic retention indices, and various physical properties of molecules.7-11 The present article reviews applications of quantum chemical descriptors in the development of QSAR/QSPR dealing with the chemical, physical, biochemical, and pharmacological properties of compounds.

http://depa.fquim.unam.mx/amyd//archivero/TrabajoFINAL2013-1_21514.pdf

Quantum-Chemical Descriptors in QSAR/QSPR Studies

Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

/pdf/crystal-structure-of-the-u-opioid-receptor-bound-to-a-3114f9v1hs.pdf

Crystal structure of the µ-opioid receptor bound to a morphinan antagonist

Most drugs have been discovered in random screens or by exploiting information about macromolecular receptors One source of this information is in the structures of critical proteins and nucleic acids The structure-based approach to design couples this information with specialized computer programs to propose novel enzyme inhibitors and other therapeutic agents Iterated design cycles have produced compounds now in clinical trials The combination of molecular structure determination and computation is emerging as an important tool for drug development These ideas will be applied to acquired immunodeficiency syndrome (AIDS) and bacterial drug resistance

https://science.sciencemag.org/content/sci/257/5073/1078.full.pdf

Structure-based strategies for drug design and discovery.

Computational modeling approaches to structure-function analysis of G protein-coupled receptors.

The aim of this study was to investigate the molecular changes associated with the transition of the human oxytocin receptor from its inactive to its active states Mutation of the conserved arginine of the glutamate/aspartate-arginine-tyrosine motif located in the second intracellular domain gave rise to the first known constitutively active oxytocin receptor (R137A), whereas mutation of the aspartic acid located in the second transmembrane domain led to an inactive receptor (D85A) The structural features of the constitutively active and inactive receptor mutants were compared with those of the wild type in its free and agonist-bound states The results suggest that, although differently triggered, the activation process induced by the agonist and the activating mutation are characterized by the opening of a solvent exposed site formed by the 2nd intracellular loop, the cytosolic extension of helix 5, and the 3rd intracellular loop; on the contrary, the D85A mutation prevents oxytocin from triggering the opening of a cytosolic site On the basis of these findings, we hypothesize that this cytosolic crevice plays an important role in G protein recognition Finally, comparative analysis of the free- and agonist-bound forms of the wild-type oxytocin receptor and α1B adrenergic receptor suggests that the highly conserved polar amino acids and the seven helices play similar mechanistic roles in the different G protein-coupled receptors

Activation Mechanism of Human Oxytocin Receptor: A Combined Study of Experimental and Computer-Simulated Mutagenesis

Electrostatic Analysis and Brownian Dynamics Simulation of the Association of Plastocyanin and Cytochrome F

Update 1 of: Computational Modeling Approaches to Structure Function Analysis of G Protein-Coupled Receptors Francesca Fanelli* and Pier G. De Benedetti DulbeccoTelethon Institute and Department ofChemistry, University ofModena and Reggio Emilia, via Campi 183, 41125Modena, Italy This is a Chemical Reviews Perennial Review. The root paper of this title was published in Chem. Rev., 2005, 105(9), 3297 3351, DOI: 10.1021/cr000095n; Published August 25, 2005. Updates to the text appear in red type.

Update 1 of: computational modeling approaches to structure-function analysis of G protein-coupled receptors.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2896%2901286-0

Pier G. De Benedetti

Papers

Computational modeling approaches to structure-function analysis of G protein-coupled receptors.

Activation Mechanism of Human Oxytocin Receptor: A Combined Study of Experimental and Computer-Simulated Mutagenesis

Electrostatic Analysis and Brownian Dynamics Simulation of the Association of Plastocyanin and Cytochrome F

Update 1 of: computational modeling approaches to structure-function analysis of G protein-coupled receptors.

Amino acids of the α1B-adrenergic receptor involved in agonist binding: differences in docking catecholamines to receptor subtypes