Development of a common 3D pharmacophore for δ-opioid recognition from peptides and non-peptides using a novel computer program

A unified three-dimensional (3D) pharmacophore for recognition of the -opioid receptorby families of structurally diverse -opioid ligands, including peptides and non-peptides,has been determined. An additional structural feature required for -selectivity was alsocharacterized using a subset of these ligands that are highly selective for the -opioidreceptor. To obtain these pharmacophores, we have used a recently developed computerprogram that performs systematic and automated comparisons of molecules to determinewhether any common 3D relationships exist among candidate recognition moieties in high-affinity analogs. All the low-energy conformations of each ligand are included in thesecomparisons. The program developed should be applicable in general to molecular super-imposition problems in rational drug design and to develop both 3D recognition and activationpharmacophores for any receptor for which high- and low-affinity analogs and agonists andantagonists have been identified.     

Binding of α-hydroxy-β-amino acid inhibitors to methionine aminopeptidase. The performance of two types of scoring functions

The binding mode of a recently described set of -hydroxy--amino acid inhibitors of methionine aminopeptidase type 2 is suggested in the present work. The binding mode is supported by analysis of published structures of transition state analogues co-crystallised with E. coli methionine aminopeptidase and by a comparison of molecular interaction fields calculated using GRID for E. coli and human methionine aminopeptidase. Based on the suggested binding mode two types of scoring functions have been evaluated and compared. These are the commercially available consensus score, CScore, and scoring of the ligands employing energies calculated using the Merck Molecular Force Field (MMFF). Enriched subsets of ligands were obtained when using CScore, but these scores could not be used to assess the relative affinities of individual compounds. Although still not sufficiently accurate for reliable predictive purposes, an improved correlation was obtained between structure and affinity using a combined force field energy including contributions from solvation and conformational energy penalty for binding.     

基于药效团模型从中草药数据库中搜索gpIIb/IIIa受体抑制剂

选择20 个3,4-二氢-1(1H)-异喹啉酮类gpIIb/IIIa受体抑制剂作为训练集, 利用Catalyst软件包建立了gpIIb/IIIa受体抑制剂三维药效团模型. 探讨了药效团作用模式. 并通过建立的可靠性最佳的药效团模型(线性回归系数r=0.7715), 从中草药数据库中虚拟筛选了gpIIb/IIIa受体抑制剂, 通过实验活性测定得到了8个抑制ADP活化全血血小板聚集的IC50从40到100 μmol·L-1的化合物, 进一步证明了所建药效团模型的有效性.     

Theoretical studies on the conformation of saccharides

Conformations of 2-methoxytetrahydropyran as a model for the six-membered ring in aldopyranosides have been calculated by the PCILO method using the algorithm of the conjugated gradient to optimize the geometry. The calculated geometry of the fourteen basic forms of 2-methoxytetrahydropyran was found to be in agreement with the available data obtained by X-ray diffraction of pyranosides. The results indicate differences in the geometry of 2-methoxytetrahydropyran resulting from the change of the axial vs. equatorial position of the methoxyl group. These changes are particularly meaningful in the values of bond angles and they are in agreement with the anomeric and exoanomeric effects. The experimentally found differences in the energies of an axial (⁴ C ₁) and equatorial (¹ C ₄) conformer, G = 2.9–3.7 kJ/mol, and the dipole moment, = 1.20 ± 0.05 D (1D = 3.33 10^–30mAs) agree well with the calculated values E = 3.18 kJ/mol and <> = 1.18 D which, in turn, suggest that the axial conformer is preferred over the equatorial one by a ratio a:e = 78:22.     

The Comparison of the Orientation of Sodium 3-Hydroxy-2-Naphthalenecarboxylate in the Cavity of β-Cyclodextrin and Heptakis-(2,3,6-Tri-O-Methyl)-β-Cyclodextrin

Conformational analysis of inclusion complexes of sodium 3-hydroxy-2-naphthalenecarboxylate with -cyclodextrin and heptakis-(2,3,6-tri-o-methyl)--cyclodextrin in D₂O was investigated by 1D and 2D ¹HNMR measurements. The results show that part of the naphthyl group of sodium 3-hydroxy-2-naphthalenecarboxylate is situated in the 2,3-OH side of the -cyclodextrin cavity asymmetrically while the whole naphthyl group is included in the heptakis-(2,3,6-tri-o-methyl)--cyclodextrin cavity with the caboxylate and hydroxy group close to the 6-OCH₃ group.     

Pseudorotaxanes of β-Cyclodextrin with Diamino End-functionalized Oligo-phenyl and -benzyl Compounds in Solution and in the Solid State

-Cyclodextrin forms a 1:1 host:guest inclusion complex ([2]pseudorotaxane) with 4-[2-(4-aminophenyl)ethyl]-benzenamine (1) in water as determined by 1D and 2D NMRexperiments. In the crystalline state, the structure of the complex has revealed a 2:2 stoichiometry, with two CD molecules forming head-to-head dimers byH-bonds between the secondary O3 hydroxyl groups and enclosing two molecules of the guest. The packing mode of the present complex is encountered for the first time, since it does not belong to any of the four known packing types of the dimeric CD inclusion complexes. On the other hand,N ¹,N ⁴-bis(4-aminophenyl)-1,4-benzenedimethanamine 2), which is longer than 1 by a phenylene diamine unit, has not afforded any crystals, at present, however it threads into CD in aqueous solution forming most probably [2]- and [3]pseudorotaxanes. The solution structures and the equilibria in this system are investigated.     

Constrained search of conformational hyperspace

Summary We introduce a new method for determining pharmacophore or active site geometries by analysis of the structures of a series of active compounds. The method, constrained search, and the key concepts on which it is based, is described and illustrated by its application to 28 potent inhibitors of angiotensin-converting enzyme (ACE). The data set is one utilized by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3–16] to determine a unique geometry for the active site. Our experiment validated the previously reported results, obtained by a systematic search, while reducing the computer time requirement by more than two orders of magnitude. The experiment also identified a previously unrecognized alternative active site geometry for the ACE series.     

Quantum-chemical study of allylic compounds with two bonded heavy atoms

It has been shown by the CNDO method that the bathochromic shift of the long-wave absorption band in the transition from allylstannane to compounds of the type C=C-C-Sn-X and C=C-Sn-X (where X is a heavy atom) is connected with the formation of a low-energy vacant *_S-X orbital, localized mainly in the region of the Sn-X chemical bond, and of an occupied _Sn-X orbital, the energy of which is somewhat higher than of the _C-Sn orbital. The dependence of the position of the long-wave absorbance region on conformation is related to the fact that, in planar and nonplanar conformers, the long-wave transitions are of a different type ( * and *, respectively); the bathochromic shift is determined to a large degree by the difference in the energies of the highest occupied MO ( - ) in the s-trans form. In the nonplanar conformers the heavy atom orbitals interact with the -orbital of the ethylene moiety through the bridge group; this leads to a significant delocalization of the HOMO and to a considerable change in its energy. On the other hand, their interaction with the *-orbital in compounds of the C=C-C-Sn-X type is very low and does not favor the delocalization of lower vacant MO. In vinyldistannane the *-orbital is noticeably delocalized, due to the interaction with the *_Sn-Sn orbital in planar and with the *_Sn-Sn orbital in nonplanar conformers.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 3, pp. 636–641, March, 1992.     

Synthesis and Properties of 1,3,5-Tris(phenoxymethyl)-2,4,6-triethylbenzenes as NH 4 + Ionophores

The synthesis, spectroscopic characterization, and potentiometricmeasurements of new 1,3,5-trisphenoxy-2,4,6-triethylbenzenesare described. The cation binding abilities oftrisphenoxy-2,4,6-triethylbenzenes were strongly dependenton the substituents introduced on the phenoxy units: thereceptors with electron-donating alkoxy groups (–OCH₃and –OCH₂C₆H₅) provided similar potentiometricperformance to that of nonactin in PVC-based, ion-selectivemembrane electrodes. The trisphenoxy-2,4,6-triethylbenzenereceptors with ether groups on ortho and meta positions ofphenoxy units exhibit almost identical cation recognitionproperties in the PVC membranes. It is postulated that theelectron-donating nature of the alkoxy substituents increases theelectron density in the phenoxy units, resulting in increasedcation- interactions.     

Bonding criteria for diatomic molecular orbitals and inter-relations among them

Bonding criteria for molecular orbitals in diatomic molecules are discussed. An orbital force criterion is shown to have several conceptual and practical advantages, providing a basis for the investigation of inter-relations among many of the commonly employed criteria.It is found that interconsistency among those criteria is guaranteed, within the framework of Koopmans' Theorem, if the orbital energies are monotonic in the range (R _e, ).The application of the orbital force criterion to the second row homonuclear diatomics exhibits reasonable chemical trends concerning the valence-shell orbitals, as well as indications of a slightly antibonding nature of the inner orbitals.Based on a section of a thesis to be submitted by Y.T. to the Senate of the Technion-Israel Institute of Technology, in partial fulfilment of the requirements for the D.Sc. degree     

Formulation and Preliminary in vivo Testing of Rufloxacin-Cyclodextrin Ophthalmic Solutions

Aim of the present work was to investigate the effect of somecyclodextrins (CDs) on the solubility and ocular bioavailability of rufloxacin base (RUF), with theultimate goal of developing an ophthalmic formulation. Phase solubility studies of RUF inpH 7.4 buffer were carried out in the presence of -cyclodextrin (-CD),hydroxypropyl--cyclodextrin (HP--CD) and -cyclodextrin(-CD). The effect of hydroxypropyl methylcellulose (HPMC) on RUF solubility was evaluated after heating the solutionscontaining HP--CD at 120 °C.A significant enhancement of RUF solubility was achieved by associatingthe drug with CDs, particularly HP--CD. This CD formed with RUF a less stablecomplex than that formed by -CD, but did not suffer the solubility limitations ofthe parent CD, and showed a higher solubilizing capacity than -CD. Addition of 0.25%(w/v) HPMC to solutions containing HP--CD increased the solubilizing effect of this CD,thus allowing reduction of the amount necessary for solubilization of 0.3% (w/v) RUF.Preliminary pharmacokinetic data in rabbits indicated that theocular bioavailability of 0.3% (w/v) RUF solubilized by HP--CD was higher when compared witha 0.3% (w/v) RUF suspension used as reference.     

SCF perturbation theory for unimolecular reactions

A CNDO/2 SCF perturbation theory is presented for interpreting the form of CNDO/2 potential energy surfaces of unimolecular reactions. The analysis is performed by calculating the energy change E arising from a distortion of the molecular geometry along the reaction coordinate. E is decomposed into different perturbational contributions which are appropriate for an interpretation of the perturbation energy E. Moreover, E is resolved into energy parts arising from a single occupied orbital and contributions due to pairwise orbital interactions. In this way one evaluates numerically how the form of the occupied and unoccupied orbitals determines the magnitude of E. If the distortion occurs along a definite symmetry coordinate, group-theoretical arguments can be applied to discuss the magnitude of characteristic components of the perturbation energy. The SCF perturbation theory is used to analyze the isomerization of ethylene, cis-2-butene and cis-2-butenenitrile.This work was partially supported by Nato-Grant No. 1072     

Microhardness of α- and β-modified isotactic polypropylene at the initial stages of plastic deformation: analysis of micromechanical processes

The microindentation hardness,H, of uniaxially deformed isotactic polypropylene samples was determined near the neck region, as a function of the draw ratio. The microhardness technique appears to be a valuable tool to describe mechanical properties in localized regions within a material and is capable of following changes in the semicrystalline structure during deformation. Differences in the microhardness behaviour of the two types of polymorphic forms, and , of isotactic polypropylene are discussed in terms of the two specific types of morphology, i.e. the cross-hatched arrangement of the crystalline lamellae for the form and the parallel lamellar stacking for the form. The changes of H as a function of are shown to be in accordance with the transformation in the neck from the spherulitic into the fibre structure. The steep H-decrease observed in the neck region is discussed in the light of the nanomechanical processes as revealed by scanning electron microscopy. These include lamellar separation, micro-void formation and fibrillation. Finally, microindentation experiments carried out in the neck allow an estimation of the local draw ratio at which the maximum pore content in the polypropylene samples occurs.     

Membrane transport of dicarboxylic and α-hydroxy carboxylic acids induced by α-amino phosphonates

New -amino phosphonates containing different alkyl and aryl substituents at the -carbon atom were synthesized in high yields by the Kabachnik—Fields and Pudovik reactions. These compounds were studied as carriers of several -hydroxy carboxylic and dicarboxylic acids through liquid impregnated membranes. These -amino phosphonates studied are capable of molecular recognition of oxalic acid among structurally similar -hydroxy carboxylic and dicarboxylic acids. The efficiency and selectivity of mass transfer of oxalic acid increase with an increase in the lipophilicity of the -amino phosphonate.     

Bilirubin conformational enantiomer selection in sodium deoxycholate chiral micelles

Intramolecularly hydrogen-bonded, bichromophoric tetrapyrrole pigments, bilirubin-IX and mesobilirubin-XIII, adopt either of two enantiomeric conformations which are in dynamic equilibrium in solution. InpH 8 aqueous sodium deoxycholate solutions, chiral micelles preferentially select one conformational enantiomer, and the solutions exhibit a bisignate circular dichroism Cotton effect in the vicinity of the bilirubin long wavelength electronic transition. Exciton coupling theory indicates a predominance of the left-handed (or negative) chirality bilirubin conformational enantiomer.     

Reactivity of pyrrole pigments,XXI: Structure and reactivity of Cu(II) and Zn(II) bilindione chelates

Summary Several Mn, Cu, and Zn chelates of etiobiliverdin-IV-, mesobiliverdin-IX, and its dimethyl ester are studied. The results show that the chemical constitution of the Cu biliverdin chelate corresponds to a formal metal oxidation state of (II) coordinated to a neutral radical of the NH trideprotonated biliverdin. The reactivity of the Cu(II) bilindione chelates in nucleophilic solvents agrees with that expected for a neutral radical structure of the ligand; in CH₃OH, they undergo oxidation towards dimethoxybilipurpurins. The magnetic behaviour of Cu(II) etiobiliverdinate-IV- in the solid state shows an intramolecular weak antiferromagnetic coupling d⁹Cu-to--radical (J=–23 cm^–1) and an intermolecular weak antiferromagnetic coupling -radical-to--radical (J=–45 cm^–1). The analogy of this magnetic behaviour to that of the cation radical of metalloporphyrins is discussed.

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Reaktivität von Pyrrolpigmenten, 21. Mitt.: Struktur und Reaktivität von Cu(II)- und Zn(II)-Chelaten von Bilindionen

Zusammenfassung Einige Mn, Cu and Zn Chelate von Etiobiliverdin-IV-, Mesobiliverdin-IX und seinem Dimethylester werden untersucht. Im Komplex koordiniert ein Metallatom (mit der Formalladung II) mit einem Neutralradikal des dreifach NH-deprotonierten Bilindions. Die Reaktivität des Komplexes gegenüber nukleophilen Lösungmitteln entspricht erwartungsgemäß dem eines neutralen -Radikals; in CH₃OH wird er zu Dimethoxybilipurpurin oxidiert. Bei Cu(II)-Etiobiliverdinat-IV beobachtet man im festen Zustand neben schwacher, antiferromagnetischer Kupplung zwischen d⁹Cu und -Radikal (J=–23 cm^–1) auch eine schwache, intermolekulare, antiferromagnetische Wechselwirkung zwischen zwei -Radikalen (J=–45 cm^–1). Dieses magnetische Verhalten wird dem des -Kationradikals von Metalloporphyrinen gegenübergestellt.

     

Effect of hydrophobic amino acids on the conformational change of decapeptides in micellar environments

A series of peptides containing various hydrophobic amino acids [methionine (Met), leucine (Leu), norleucine (Nle), phenylalanine (Phe), 2-aminooctanoic acid (Aoc), and 2-aminodecanoic acid (Ade)] were synthesized and their conformations were studied using circular dichroism (CD) spectroscopy in different solvents such as water, methanol, and aqueous solution of ammonium tetradecanesulfonate. Peptides containing hydrophobic amino acids with linear side chains formed -sheets in water and methanol. Electrostatic interaction between the charged side chain (lysine) and a micelle consisting of an anionic surfactant, ammonium tetradecanesulfonate, is necessary for the formation of -helices in micellar environments. The conformational transition from -helix to -sheet structure required moderate hydrophobicity and linear side chains. This conformational transition depended on the surfactant concentration.     

Effect of fusion conditions ofβ-polypropylene on the new crystallization

The new crystallization of -modification of polypropylene (-PP) was studied after melring as a function of the final temperature of fusion (T _F ). The new crystallization, thermal characteristics, polymorphic composition, and structure of recrystallized samples were highly influenced by theT _F level. As a function ofT _F , three characteristic regions were outlined: Region I below the melting point of -modification, region II between the melting points of - and -modifications, and region III above the melting point of -modification. In the vicinity of the melting points of both modifications, two narrow transition regions are observed where the crystallization and structural characteristics changed abruptly withT _F . AtT _F values in region I, recrystallization of -modification proceeded without any change in the modification. IfT _F fell in region II, the sample crystallized newly into -modification. The optically negative -ring-spherulites were replaced by positive microclusters of -modification and a marked structural memory effect was observed. In region III, the above characteristic became invariant withT _F (region of blank melt). These observations may be interpreted by the role of self nuclei.     

Sulfur heterocycles. 13. Oxidative chlorination of β-thiolactones. A novel synthesis of β-(chlorosulfinyl)alkanoyl chlorides and 1,2-oxathiolan-5-one 2-oxides

Chlorination of -thiolactones with chlorine or sulfuryl chloride in acetic anhydride at a reactant ratio (RR) of 1:2:1 gives -(chlorosulfinyl)alkanoyl chlorides in 75–89% yields. Oxidative chlorination of -thiolactones with RR of 1:3:2 affords -(chlorosulfinyl)alkanoyl chlorides and cyclic sulfinic anhydrides (1,2-oxathiolan-5-one 2-oxides). The optimum RR for the preparation of 1,2-oxathiolan-5-one 2-oxides is 1:2:2. Hydrolysis of -chloro--(chlorosulfinyl)carbonyl chlorides has given novel -chlorinated sulfinocarboxylic acids.For communication 12, see [1].A. N. Nesmeyanov Institute of Heteroorganic Chemistry, Russian Academy of Sciences, 117813 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 9, pp. 2153–2158, September, 1992.     

Calculation of some electronic excited states of formaldehyde

The optimized MO's of several excited states of formaldehyde have been calculated by means of a large basis set of modified Gaussian functions; particular attention has been paid to the * transition. The total energy of the various states has been obtained as the sum of the SCF and correlation energies; the last one has been calculated as a functional of the electronic density. The calculated values for the transition energies are in good agreement with the experiment. A strong interaction of the * state with the continuum is evidentiated; this fact can justify the absence of the * band in the absorption spectrum.