Development and validation of opioid ligand–receptor interaction models: The structural basis of mu vs. delta selectivity

Opioid receptor binding conformations for two structurally related, conformationally constrained tetrapeptides, JOM-6 (µ receptor selective) and JOM-13 (δ receptor selective), were deduced using conformational analysis of these ligands and analogs with additional conformational restrictions. Docking of these ligands in their binding conformations to opioid receptor structural models, based upon the published rhodopsin X-ray structure, implicates specific structural features of the µ and δ receptor ligand binding sites as forming the basis for the µ selectivity of JOM-6 and the δ selectivity of JOM-13. In particular, the presence of E229 in the µ receptor (in place of the corresponding D210 of the δ receptor) causes an adverse electrostatic interaction with C-terminal carboxylate-containing ligands, resulting in the observed preference of ligands with an uncharged C-terminus for the µ receptor. In addition, the requirement that the Phe 3 side chain of JOM-13 assume a gauche orientation for optimal δ binding, whereas the Phe 3 side chain of JOM-6 must be in a trans orientation for high-affinity µ binding can be largely attributed to the steric effect of replacement of L300 of the δ receptor by W318 of the µ receptor. Testing this hypothesis by examining the binding of JOM-6 and several of its key analogs with specific µ receptor mutants is described. Our initial results are consistent with the proposed ligand–receptor interaction models.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73528/1/j.1399-3011.2002.21061.x.pd

Modulation of Opioid Receptor Ligand Affinity and Efficacy Using Active and Inactive State Receptor Models

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94299/1/cbdd.12014.pd

The role of hydrophobic interactions in positioning of peripheral proteins in membranes

Abstract Background Three-dimensional (3D) structures of numerous peripheral membrane proteins have been determined. Biological activity, stability, and conformations of these proteins depend on their spatial positions with respect to the lipid bilayer. However, these positions are usually undetermined. Results We report the first large-scale computational study of monotopic/peripheral proteins with known 3D structures. The optimal translational and rotational positions of 476 proteins are determined by minimizing energy of protein transfer from water to the lipid bilayer, which is approximated by a hydrocarbon slab with a decadiene-like polarity and interfacial regions characterized by water-permeation profiles. Predicted membrane-binding sites, protein tilt angles and membrane penetration depths are consistent with spin-labeling, chemical modification, fluorescence, NMR, mutagenesis, and other experimental studies of 53 peripheral proteins and peptides. Experimental membrane binding affinities of peripheral proteins were reproduced in cases that did not involve a helix-coil transition, specific binding of lipids, or a predominantly electrostatic association. Coordinates of all examined peripheral proteins and peptides with the calculated hydrophobic membrane boundaries, subcellular localization, topology, structural classification, and experimental references are available through the Orientations of Proteins in Membranes (OPM) database. Conclusion Positions of diverse peripheral proteins and peptides in the lipid bilayer can be accurately predicted using their 3D structures that represent a proper membrane-bound conformation and oligomeric state, and have membrane binding elements present. The success of the implicit solvation model suggests that hydrophobic interactions are usually sufficient to determine the spatial position of a protein in the membrane, even when electrostatic interactions or specific binding of lipids are substantial. Our results demonstrate that most peripheral proteins not only interact with the membrane surface, but penetrate through the interfacial region and reach the hydrocarbon interior, which is consistent with published experimental studies.http://deepblue.lib.umich.edu/bitstream/2027.42/116604/1/12900_2007_Article_125.pd

Study of the association of gene polymorphism with the risk of non-communicable diseases in martial artists

Objective: to study the effect of genetic polymorphisms: rs rs9939609 (FTO gene), rs4994 (ADRB3 gene), rs1042713 (ADRB2 gene), rs2228570 (VDR gene), rs1801133 (MTHFR gene) on anthropometric and lipid metabolism indicators in athletes representing martial arts.Materials and methods: studies of anthropometric and biochemical parameters, genetic polymorphisms were carried out in 120 athletes (101 men and 19 women) who are engaged in martial arts. Anthropometric studies were performed by measuring height (cm), body weight (kg), followed by calculating body mass index (BMI, kg / m2). Biochemical nutritional status markers were determined using the ABX Pentra 400 analyzer (HORIBA ABX SAS, France) in an automatic mode. Genotyping was performed using allele­specific amplification using TaqMan probes complementary to polymorphic DNA regions and real­time detection of the results using reagent kits from Syntol, Russia. Studies were performed on the device CFX96 Real Time System (Bio­Rad, USA). Statistical processing of the results was performed using the PASW Statistics 20 system.Results: as a result of generic Diovan athletes martial artists on the risk of non­communicable diseases, discovered that the frequency of allele A of rs9939609 polymorphism of the FTO gene they have is 43.9 %, allele polymorphism rs4994 ADRB3 gene — 10.9 %, G allele of rs1042713 ADRB2 gene polymorphism — 52.6 %, G allele of the polymorphism rs2228570 VDR gene with 44.9 % and allele t of rs1801133 in the MTHFR gene to 36.7 %. An association was found between the value of anthropometric indicators in male martial artists and the presence of polymorphisms rs9939609 (FTO), rs1042713 (ADRB2) and rs2228570 (VDR).Conclusions: the reason for the identified dyslipidemia in martial artists may be not only the previously detected violations of the structure of their nutrition, but also the presence of certain genetic polymorphisms, in particular, rs4994 of the ADRB3 gene and rs1042713 of the ADRB2 gene

Design of high affinity cyclic pentapeptide ligands for Κ-opioid receptors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73319/1/j.1399-3011.2005.00295.x.pd

Evaluation of the actual nutrition and nutritional status of combat athletes

Objective: to evaluate the actual nutrition and nutritional status of combat athletes. Materials and methods: the evaluation of the actual nutrition of 129 athletes involved in martial arts: 86 men (average age 22.1±0.5 years) and 43 women (average age 22.2±0.8 years) were carried out. The actual nutrition was investigated by the method of 24-hour (daily) reproduction of food intake. The biochemical and anthropometric markers of the nutritional status were evaluated; body mass index (BMI) and component body composition were assessed using bioimpedansometry. Results: results of the study showed unbalanced nutrition of athletes - excessive consumption of animal fat, cholesterol, sodium, and added sugar (including high-fat dairy products and confectionery).The nutrition analysis of combat athletes revealed a lack of vitamins B, magnesium, calcium, which was associated with low consumption of dairy products, fruits and vegetables. Disturbances in the nutritional structure caused unfavorable changes in some participants, such as an increase in BMI, the amount of adipose tissue, dyslipidemia, against the background of insufficient efficiency of the recovery processes of athletes and the risk of overwork. Conclusions: violation of the nutritional structure of athletes leads to development of pathological changes in nutritional status, which include increase of BMI and the amount of adipose tissue, dyslipidemia due to the lack of efficiency of recovery processes of athletes and the risk of overwork. The noted violations of nutrition and nutritional status are a risk factor for the development of alimentary-dependent diseases (cardiovascular pathology, obesity, osteoporosis, etc.)

Nutritional habits of combat athletes

The review presents modern data characterizing the features of the energy exchange of athletes engaged in combat sport. The general principles of diet formation for combat athletes taking into account the basis of optimal nutrition, dependence on the period of sports activity (training, competition, and recovery), the duration and intensity of physical exertion are described. Based on results of recent studies published by Russian and foreign authors, the substantiation for the energy density of chemical composition of the diet (the content of proteins, fats, carbohydrates, vitamins, macro- and microelement) and hydration regime of combat athletes is given. The issues of food distribution during the day are affected, depending on the training and competitive process. Particular attention is paid to the use of specialized products and dietary supplements, as well as personalization of nutrition, which is based on individual studying of the nutritional status of combat athletes

Nutritional habits of athletes in speed-and-strength sports

Speed-and-strength sports differ from other sports because of its short time and very intense physical activity. ^e review provides a literature analysis of the effect of nutrients on the metabolic processes that occur during the occupation of these sports. During the training of athletes generally anaerobic mechanisms of muscular work dominate, so the nutrition of athletes focuses on the consumption of foods with high protein content and essential amino acids. ^e article describes general principles of diet constructing for athletes that should correspond to the basics of optimal nutrition, depend on the period of sport activity (training, competition, recovery), the duration and intensity of physical exertion, etc. Based on the results of recent studies published by domestic and foreign authors, the substantiation of the energy value and the chemical composition of the diet (the content of proteins, fats, carbohydrates, vitamins, macro- and microelements), as well as the formation of diets and drinking regime for highly skilled athletes involved in speed-and-strength sports is given

Translation of structure‐activity relationships from cyclic mixed efficacy opioid peptides to linear analogues

Most opioid analgesics used in the treatment of pain are mu opioid receptor (MOR) agonists. While effective, there are significant drawbacks to opioid use, including the development of tolerance and dependence. However, the coadministration of a MOR agonist with a delta opioid receptor (DOR) antagonist slows the development of MOR‐related side effects, while maintaining analgesia. We have previously reported a series of cyclic mixed efficacy MOR agonist/DOR antagonist ligands. Here we describe the transfer of key features from these cyclic analogs to linear sequences. Using the linear MOR/DOR agonist, Tyr‐DThr‐Gly‐Phe‐Leu‐Ser‐NH 2 ( DTLES ), as a lead scaffold, we replaced Phe 4 with bulkier and/or constrained aromatic residues shown to confer DOR antagonism in our cyclic ligands. These replacements failed to confer DOR antagonism in the DTLES analogs, presumably because the more flexible linear ligands can adopt binding poses that will fit in the narrow binding pocket of the active conformations of both MOR and DOR. Nonetheless, the pharmacological profile observed in this series, high affinity and efficacy for MOR and DOR with selectivity relative to KOR, has also been shown to reduce the development of unwanted side effects. We further modified our lead MOR/DOR agonist with a C‐terminal glucoserine to improve bioavailability. The resulting ligand displayed high efficacy and potency at both MOR and DOR and no efficacy at KOR. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 107–114, 2014.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102641/1/bip22437.pd