Molecular modeling of interactions of the non-peptide antagonist YM087 with the human vasopressin V1a,V2 receptors and with oxytocin receptors

The nonapeptide hormones arginine vasopressin (CYFQNCPRG-NH₂, AVP) and oxytocin (CYIQNCPLG-NH₂, OT), control many essential functions in mammals. Their main activities include the urine concentration (via stimulation of AVP V2 receptors, V2R, in the kidneys), blood pressure regulation (via stimulation of vascular V1a AVP receptors, V1aR), ACTH control (via stimulation of V1b receptors, V1bR, in the pituitary) and labor and lactation control (via stimulation of OT receptors, OTR, in the uterus and nipples, respectively). All four receptor subtypes belong to the GTP-binding (G) protein-coupled receptor (GPCR) family. This work consists of docking of YM087, a potent non-peptide V1aR and V2R – but not OTR – antagonist, into the receptor models based on relatively new theoretical templates of rhodopsin (RD) and opiate receptors, proposed by Mosberg et al. (Univ. of Michigan, Ann Arbor, USA). It is simultaneously demonstrated that this RD template satisfactorily compares with the first historical GPCR structure of bovine rhodopsin (Palczewski et al., 2000) and that homology-modeling of V2R, V1aR and OTR using opiate receptors as templates is rational, based on relatively high (20–60%) sequence homology among the set of 4 neurophyseal and 4 opiate receptors. YM087 was computer-docked to V1aR, V2R and OTR using the AutoDock (Olson et al., Scripps Research Institute, La Jolla, USA) and subsequently relaxed using restrained simulated annealing and molecular dynamics, as implemented in AMBER program (Kollman et al., University of California, San Francisco, USA). From about 80 diverse configurations, sampled for each of the three ligand/receptor systems, 3 best energy-relaxed complexes were selected for mutual comparisons. Similar docking modes were found for the YM087/V1aR and YM087/V2R complexes, diverse from those of the YM087/OTR complexes, in agreement with the molecular affinity data.     

Molecular modeling of the neurophysin I/oxytocin complex

Neurophysins I and II (NPI and NPII) act in the neurosecretory granules as carrier proteinsfor the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively. The NPI/OTfunctional unit, believed to be an (NPI/OT)2 heterotetramer, was modeled using low-resolution structure information, viz. the C carbon atom coordinates of the homologousNPII/dipeptide complex (file 1BN2 in the Brookhaven Protein Databank) as a template. Itsall-atom representation was obtained using standard modeling tools available within theINSIGHT/Biopolymer modules supplied by Biosym Technologies Inc. A conformation of theNPI-bound OT, similar to that recently proposed in a transfer NOE experiment, was dockedinto the ligand-binding site by a superposition of its Cys1-Tyr2 fragment onto the equivalentportion of the dipeptide in the template. The starting complex for the initial refinements wasprepared by two alternative strategies, termed Model I and Model II, each ending with a100 ps molecular dynamics (MD) simulation in water using the AMBER 4.1 force field. The freehomodimer NPI2 was obtained by removal of the two OT subunits from their sites, followedby a similar structure refinement. The use of Model I, consisting of a constrained simulatedannealing, resulted in a structure remarkably similar to both the NPII/dipeptide complex anda recently published solid-state structure of the NPII/OT complex. Thus, Model I isrecommended as the method of choice for the preparation of the starting all-atom data forMD. The MD simulations indicate that, both in the homodimer and in the heterotetramer, the310-helices demonstrate an increased mobility relative to the remaining body of the protein.Also, the C-terminal domains in the NPI2 homodimer are more mobile than the N-terminalones. Finally, a distinct intermonomer interaction is identified, concentrated around its mostprominent, although not unique, contribution provided by an H-bond from Ser25O in one NPI unit to Glu81 O in the other unit. This interaction is present in the heterotetramer(NPI/OT)2 and absent or weak in the NPI2 homodimer. We speculate that this interaction,along with the increased mobility of the 310-helices and the carboxy domains, may contributeto the allosteric communication between ligand binding and NPI dimerization.     

Synthesis and biological evaluation of novel phenothiazine derivatives as non-peptide arginine vasopressin V2 receptor antagonists

A series of novel phenothiazine derivatives was synthesized and tested for arginine vasopressin receptor antagonist activity. They were synthesized as novel arginine vasopressin receptor antagonists from phenothiazine as a scaffold via successive acylation, reduction and acylation reactions. Their structures were characterized by 1HNMR, 13CNMRandHRMS, and biological activitywas evaluated by in vitro and in vivo studies. The in vitro binding assay indicated that several compounds are potent selective V2 receptor antagonists. Compounds with promising binding affinity to V2 receptors were selected to conduct the in vivo diuretic studies on Sprague-Dawley rats. Among them, 1n, 1r, 1t and 1v exhibited excellent diuretic activity, especially 1r and 1v. Therefore, 1r and 1v are potent novelAVP V2receptor antagonist candidates.     

Comparative analysis of the conformational profile of substance P using simulated annealing and molecular dynamics

The present study describes an extensive conformational search of substance P using two different computational methods. On the one hand, the peptide was studied using the iterative simulated annealing, and on the other, molecular dynamics simulations at 300 and 400 K. With the former method, the peptide was studied in vacuo with a dielectric constant of 80, whereas using the latter study the peptide was studied in a box of TIP3P water molecules. Analysis of the results obtained using both methodologies was carried out using an in-house methodology using a cluster analysis method based on information theory. Comparison of the two sampling methodologies and the different environment used in the calculations is also analyzed. Finally, the conformational motifs that are characteristic of substance P in a hydrophilic environment are presented and compared with the experimental results available in the literature.     

Solution NMR spectroscopy of the human vasopressin V2 receptor, a G protein-coupled receptor

The seven-transmembrane-spanning G protein-coupled receptor (GPCR) superfamily plays many important roles in basic biology, human health, and human disease. Here, well-resolved solution NMR spectra are presented for a human GPCR, the vasopressin V2 receptor in detergent micelles. The quality of the NMR spectra indicates that backbone resonance assignments for a majority of resonances are feasible. The key to obtaining high quality spectra appears to be the coupling of methods for expressing the receptor into membranes rather than into inclusion bodies, with use of a biochemically mild lysolipid detergent for membrane extraction, protein purification, and NMR sample preparation.     

DCN1-UBE2M相互作用抑制剂的3D-QSAR、分子对接和分子动力学研究

类泛素化是一种蛋白质翻译后修饰,其异常会导致神经退行性疾病和多种肿瘤的发生,因此它被视为有希望的抗肿瘤靶标.研究表明,抑制DCN1-UBE2M相互作用可选择性阻遏类泛素化.本文基于哌啶基脲类DCN1-UBE2M相互作用抑制剂进行3D-QSAR、分子对接和分子动力学模拟研究.利用3D-QSAR中的CoMFA和CoMSIA...     

Molecular modeling of A1 and A2A adenosine receptors: comparison of rhodopsin- and beta2-adrenergic-based homology models through the docking studies

Adenosine receptors (ARs) are members of the superfamily of G protein-coupled receptors. The homology models of adenosine A1 and A2A receptors were constructed. The high-resolution X-ray structure of bovine rhodopsin and crystal structure of beta2-adrenergic receptor were used as templates. The binding sites of the A1 and A2A ARs were constructed by using data obtained from mutagenesis experiments as well as docking simulations of the respective AR antagonsists DPCPX and XAC. To compare rhodopsin- and beta2-adrenergic-based models, the binding mode of A1 (KW-3902, LUF-5437) and A2A (KW-6002, ZM-241385) ARs antagonists were also examined. The differences in the binding ability of both models were noted during the study. The beta2-adrenergic-based A2A AR model was much more capable to stabilize the ligand in the binding site cavity than the corresponding rhodopsin-based A2A AR model, however, such differences were not so clear in case of A1 AR models. It was suggested that for the A1 AR it is possible to use the crystal structure of rhodopsin as a template as well as beta2-adrenergic receptor, but for A2A AR, with the now available beta2-adrenergic receptor X-ray structure, docking studies should be avoided on the rhodopsin-based model. However, taking into account that the beta2AR shares about 31% of the residues with the AR in comparison to 21% in case of bRho, we suggest using beta2-adrenergic-based models for the A1 and A2A ARs for further in silico ligand screening also because of their generally better ability to stabilize ligands inside the binding pocket.     

Activation of β2-Adrenergic Receptor Induced by Three Catecholamine Agonists: a Docking and Molecular Dynamics Study

We studied the activation of β₂-adrenergic receptor(β₂AR) by norepinephrine, epinephrine and isoproterenol using docking and molecular dynamics(MD) simulation. The simulation was done on the assumption that β₂AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β₂AR for the three activators. We also simulated the change of the conformation of β₂AR in the transmembrane regions(TMs), in the molecular switches, and in the conserved DRY(Aspartic acid, Arginine and Tyrosine) motif. This study provides detailed information concerning the structure of β₂AR during activation process.     

VEGFR-2 与抑制剂Sunitinib 的分子对接及分子动力学研究

用分子对接方法研究了VEGFR-2 和抑制剂Sunitinib 的相互作用模式, 并对其复合物进行了10 ns 的分子动力学(Molecular Dynamics, MD)模拟. 结果表明, 抑制剂Sunitinib 能与VEGFR-2 中位于活性空腔的Glu885, Ile888, His1026,Asp1028, Asp1046 五个氨基酸残基形成疏水作用; 另外, VEGFR-2 中His1026, Cys1024, Asp1046 三个氨基酸残基能与Sunitinib 形成三个作用强度不同的氢键. 这些基团之间的相互作用是Sunitinib 抑制VEGFR-2 活性的关键因素. 研究结果可为VEGFR-2 抑制剂的结构改良、分子设计、合成提供理论参考, 并有助于寻找活性更高、效果更好的抗肿瘤药物.     

V_2O_5/CeO_2催化剂固相反应的Raman光谱研究

采用浸渍法制备了不同V2O5负载量(分别为5%和15%)的V2O5/CeO2催化剂.利用不同激发波长(514和325nm)的Raman光谱,结合X射线衍射(XRD)、紫外-可见漫反射(UV-VisDRS)和N2物理吸附技术,考察了V2O5/CeO2催化剂中V2O5和载体CeO2之间的固相反应.结果表明:催化剂在300℃焙烧时,V2O5与CeO2反应生成CeVO4,升高温度有利于固相反应的发生.样品对325nm光的吸收明显大于对514nm光的吸收,因此325nm激发波长的Raman光谱对催化剂的表层信息更为敏感.当焙烧温度较低时,由于受到表层CeVO4的阻碍,未反应的V2O5残留在载体CeO2孔道或粒子堆积孔道内部,因此514nm激发波长下能观察到V2O5的Raman峰,而表面灵敏的325nm激发波长下观察不到此现象.     

Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor

Summary Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxylate], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5-carboxylate], and Bay O 9507 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(4-nitrophenyl)-pyridine-5-carboxylate] were determined. The conformations of the 1,4-DHP rings of these activator analogues of Bay K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate] do not suggest that their activator properties are as strongly correlated with the degree of 1,4-DHP ring flattening as was indicated for members of the corresponding antagonist series. The solid state hydrogen bonding of the N(1)-H groups of the activators is not, unlike that of their antagonist counterparts, to acceptors that are directly in line with the donor. Rather, acceptor groups are positioned within ± 60 degrees of the N(1)-H bond in the vertical plane of the 1,4-DHP ring. Previously determined structure-activity relationships have indicated the importance of this N(1)-H group to the activity of the 1,4-DHP antagonists. Based on these observations, a model is advanced to describe the 1,4-DHP binding site of the voltage-gated Ca²⁺ channel and its ability to accommodate both antagonist and activator ligands.     

The Molecular Mechanism of P2Y1 Receptor Activation

Human purinergic G protein‐coupled receptor P2Y₁ (P2Y₁R) is activated by adenosine 5′‐diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y₁R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all‐atom long‐timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y₁R activation.     

V2O5-CeO2/TiO2催化剂上低温氨选择性催化还原NO的性能

考察了V2O5-CeO2/TiO2催化剂中V、Ce活性组分的担载量和焙烧温度对催化剂低温催化还原NO活性的影响及其在单独SO2、H2O和两者共存气氛下的抗毒化性能。结果表明,焙烧温度400℃下制备的5V30Ce/TiO2催化剂具有良好的低温催化还原NO活性,空速为10000h-1,165℃时NO转化率达99.2%;500℃以下低焙烧温度时,添加的Ce不与V相互作用,在催化剂表面主要以CeO2形式存在,有利于增大催化剂比表面积,增强V2O5在催化剂上的分散度,提高催化活性。而在500℃以上较高焙烧温度下,Ce与V会形成CeVO4,对活性提高不利。催化剂具有良好的低温抗水中毒性能,但受SO2毒化作用明显,其在SO2、H2O共存气氛下中毒程度较单独SO2下浅。     

熔融ZnCl2结构的分子动力学模拟研究

熔融ZnCl2作为一种离子性共价性参半的典型熔盐, 其近邻结构在实验测量和分子动力学模拟方面均作过一些研究。本文依据新近EXAFS实验结果, 比较了不同的有效势下模拟得到的径向分布函数,表明KDR势可作为一种实用势。并进一步在KDR势模拟产生的瞬态构型基础上, 使用键序参数方法研究了晶态和熔融态ZnCl2中的近邻结构。结果表明, 和晶态ZnCl2一样, 在熔融ZnCl2中存在稳定的Zn/Cl正四面体结构, 但熔态和晶态Zn/Cl近邻结构热波方差σ不同。计算表明300K晶态σ=5.0℃, 613K熔融态σ=12.2℃。也对熔融ZnCl2的网络状结构和宏观输运性质进行了讨论。     

A homology-based model of the human 5-HT2A receptor derived from an in silico activated G-protein coupled receptor

A homology-based model of the 5-HT_2A receptor was produced utilizing an activated form of the bovine rhodopsin (Rh) crystal structure [1,2]. In silico activation of the Rh structure was accomplished by isomerization of the 11-cis-retinal (1) chromophore, followed by constrained molecular dynamics to relax the resultant high energy structure. The activated form of Rh was then used as a structural template for development of a human 5-HT_2A receptor model. Both the 5-HT_2A receptor and Rh are members of the G-protein coupled receptor (GPCR) super-family. The resulting homology model of the receptor was then used for docking studies of compounds representing a cross-section of structural classes that activate the 5-HT_2A receptor, including ergolines, tryptamines, and amphetamines. The ligand/receptor complexes that ensued were refined and the final binding orientations were observed to be compatible with much of the data acquired through both diversified ligand design and site directed mutagenesis.     

Molecular Dynamics Simulations of the Interactions between Konjac Glucomannan and Carrageenan

The interactions between konjac glucomannan and carrageenan were studied with the method of molecular dynamics simulation. Part representative structure segments of KGM and two unit structures of κ-carrageenan （Fig. 2） were used as mode, and the force-field was AMBER2. The stability and sites of konjac glucomannan/carrageenan interactions in water were researched at 373 K with the following results： the potential energy （EPOT） of the mixed gel was dropped, while those of single-konjac glucomannan gel and single carrageenan were increased. The surface area （SA） of KGM in the mixed system was decreased to 1002.2A^°^2, and that of carrageenan to 800.9 A^°^2. The variations of two parameters showed that the stability of compound gel konjac glucomannan/carrageenan was improved, which is consistent with the previous studies. The sites of interactions in the mixed gel were the -OH groups on C（2）, C（4） and C（6）, the acetyl group in KGM mannose, and the -OH group on C（6） in carrageenan. The hydrogen bond was formed directly or indirectly by the bridge of waters.     

Prediction of the three-dimensional structure of the human Fas receptor by comparative molecular modeling

The Fas antigen, a cell surface receptor belonging to the tumor necrosis factor receptor(TNFR) superfamily, triggers programmed cell death (apoptosis) in the immune system. Thethree-dimensional structure of Fas and molecular details of the interaction between Fas andits ligand are currently unknown. A three-dimensional model of the Fas extracellular regionwas generated by comparative modeling. Inverse folding analysis suggested goodsequence–structure compatibility of the model and thus reasonable accuracy. Themodel was analyzed in the light of information provided by studies on TNFR and CD40,another member of the TNFR family, and the Fas ligand binding site was predicted.     

原位相分离合成V_2O_5/Fe_2V_4O_(13)纳米复合材料及其储钠性能

钠具有资源丰富、成本低廉等优势,因此钠离子电池被认为是未来替代锂离子电池的最佳候选者之一。然而,寻找合适的电极材料是当前制备高性能钠离子电池面临的难题之一。在众多候选材料中,钒酸盐材料通过引入阳离子增加钒的配位数,使得材料结构的稳定性得到提高,从而改善了钠离子电池的电化学性能。本文研究了一种原位相分离法合成V_2O_5/Fe_2V_4O_(13)纳米复合材料。通过扫描电子显微镜(SEM)、透射电子显微镜(TEM)、X射线衍射(XRD)、傅里叶变换红外光谱(FTIR)等对电极材料形貌、组成和结构进行了表征。实验结果显示,V_2O_5/Fe_2V_4O_(13)纳米复合材料相对于V2O5纳米线材料,结构更加稳定,在0.1 A·g~(-1)电流密度下,初始放电容量由295.4 m Ah·g~(-1)提升到342 m Ah·g~(-1),循环100圈容量保持率由26.6%提高到65.8%,获得了更加优异的倍率性能(在1.0 A·g~(-1)电流密度下,容量由44 m Ah·g~(-1)提高到160 m Ah·g~(-1))。因此,V_2O_5/Fe_2V_4O_(13)纳米复合材料的研究为开拓新型高性能钠离子电池负极材料拓宽了思路。