Molecule Modeling of Human Pentameric alpha(7) Neuronal Nicotinic Acetylcholine Receptor and Its Interaction with its Agonist and Competitive Antagonist

The nicotinic Acetylcholine Receptor (nAChR) is the major class of neurotransmitter receptors that is involved in many neurodegenerative conditions such as schizophrenia, Alzheimer's and Parkinson's diseases. The N-terminal region or Ligand Binding Domain (LBD) of nAChR is located at pre- and post-synaptic nervous system, which mediates synaptic transmission. nAChR acts as the drug target for agonist and competitive antagonist molecules that modulate signal transmission at the nerve terminals. Based on Acetylcholine Binding Protein (AChBP) from Lymnea stagnalis as the structural template, the homology modeling approach was carried out to build three dimensional model of the N-terminal region of human alpha(7)nAChR. This theoretical model is an assembly of five alpha(7) subunits with 5 fold axis symmetry, constituting a channel, with the binding picket present at the interface region of the subunits. alpha-netlrotoxin is a potent nAChR competitive antagonist that readily blocks the channel resulting in paralysis. The molecular interaction of alpha-Bungarotoxin, a long chain alpha-neurotoxin from (Bungarus multicinctus) and human alpha(7)nAChR seas studied. Agonists such as acetylcholine, nicotine, which are used in it diverse array of biological activities, such as enhancements of cognitive performances, were also docked with the theoretical model of human alpha(7)nAChR. These docked complexes were analyzed further for identifying the crucial residues involved i interaction. These results provide the details of interaction of agonists and competitive antagonists with three dimensional model of the N-terminal region of human alpha(7)nAChR and thereby point to the design of novel lead compounds.

Dialkyl (3-Aryl- 1,2,4-oxadiazol-5-yl)phosphonates: Synthesis and Thermal Behavior-Evidence for Monomeric Alkyl Metaphosphate

Dialkyl (3-aryl-l,2,4-oxadiazol-5-yl)phosphonate6sa -h have been obtained by 1,3-dipolar cycloaddition of arenenitrile oxides 5a-f to dialkyl phosphorocyanidates (4a and 4b) in yields ranging between 30% and 58%. A standardized method for obtaining cyanidates 4a and 4b has been established. The diethyl thiophosphorocyanidate (4c) is less reactive than 4a and 4b, only the 3-(4'-nitrophenyl) derivative 6i being obtainable. While the IR and NMFt spectra of 6a-i were unexceptional, their UV spectra showed evidence of conjugative interaction in high degrees between the phosphonate and heterocyclic moieties as well as a varying conjugative interaction between the heterocyclic and aryl moieties. The oxadiazoles 6a-h are thermally labile and yield trialkyl phosphates 7 as the only identifiable products. A mechanism based on the intermediacy of monomeric alkyl metaphosphate 11 in the formation of trialkyl phosphate was postulated, and supportive evidence in the form of trapping the metaphosphate with acetophenone has been obtained.

Constraint effects on multiple void interaction in pressure sensitive plastic solids

In this work, effects of pressure sensitive yielding and plastic dilatancy on void growth and void interaction mechanisms in fracture specimens displaying high and low constraint levels are investigated. To this end, large deformation finite element simulations are carried out with discrete voids ahead of the notch. It is observed that multiple void interaction mechanism which is favored by high initial porosity is further accelerated by pressure sensitive yielding, but is retarded by loss of constraint. The resistance curves predicted based on a simple void coalescence criterion show enhancement in fracture resistance when constraint level is low and when pressure sensitivity is suppressed.

X-ray crystal and molecular structure of a hydrated lithium picrate complex of benzo-15-crown-5; An example of non-chelation of the crown

Complexation of alkali and alkaline earth metal ions with crown ethers is well known (1) and chemical and crystallographic studies have been carried out for number of complexes (2,3). The interaction of the metal with the crown ether depends on the nature of the cation and particularly on the basicity of the anion (4) , In this paper we report the crystal and molecular structure of a lithium picrate complex of benzo-15-crown-5, the first x-ray crystallographic study of a lithlum-crown system.

Interaction of rat testis protein, TP, with nucleic acids in vitro. Fluorescence quenching, UV absorption, and thermal denaturation studies

The nucleic acid binding properties of the testis protein, TP, were studied with the help of physical techniques, namely, fluorescence quenching, UV difference absorption spectroscopy, and thermal melting. Results of quenching of tyrosine fluorescence of TP upon its binding to double-stranded and denatured rat liver nucleosome core DNA and poly(rA) suggest that the tyrosine residues of TP interact/intercalate with the bases of these nucleic acids. From the fluorescence quenching data, obtained at 50 mM NaCl concentration, the apparent association constants for binding of TP to native and denatured DNA and poly(rA) were calculated to be 4.4 X 10(3) M-1, 2.86 X 10(4) M-1, and 8.5 X 10(4) M-1, respectively. UV difference absorption spectra upon TP binding to poly(rA) and rat liver core DNA showed a TP-induced hyperchromicity at 260 nm which is suggestive of local melting of poly(rA) and DNA. The results from thermal melting studies of binding of TP to calf thymus DNA at 1 mM NaCl as well as 50 mM NaCl showed that although at 1 mM NaCl TP brings about a slight stabilization of the DNA against thermal melting, a destabilization of the DNA was observed at 50 mM NaCl. From these results it is concluded that TP, having a higher affinity for single-stranded nucleic acids, destabilizes double- stranded DNA, thus behaving like a DNA-melting protein.

Kinetic mechanism of the interaction of D-cycloserine with serine hydroxymethyltransferase

The kinetic mechanism for the interaction of D-cycloserine with serine hydroxymethyltransferase (EC2.1.2.1) from sheep liver was established by measuring changes in the activity, absorbance, and circular dichoism (CD) of the enzyme. The irreversible inhibition of the enzyme was characterized by three detectable steps: an initial rapid step followed by two successive steps with rate constants of 5.4 X s-l and 1.4 X lo4 s-l. The first step was distinguished by a rapid disappearance of the enzyme absorbance peak at 425 nm, a decrease in the enzyme activity to 25% of the uninhibited velocity, and a lowering of the CD intensity at 432 nm to about 65% of the original value. The second step of the interaction was accompanied by a complete loss of enzyme.

1-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-phenylisoquinoline

The molecular conformation of the title compound, C20H17N3, is stabilized by an intramolecular C-H center dot center dot center dot N interaction. The crystal structure shows intermolecular C-H center dot center dot center dot pi interactions. The dihedral angle between the isoquinoline unit and the phenyl ring is 11.42 (1)degrees whereas the isoquinoline unit and the pendent dimethyl pryrazole unit form a dihedral angle of 50.1 (4)degrees. Furthermore, the angle between the mean plane of the phenyl ring and the dimethyl pyrazole unit is 47.3 (6)degrees.

Intermolecular charge-transfer complexes of macrocyclic polyethers with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

The interactions of benzo-15-crown-5, dibenzo-18-crown-6, and dibenzo-24-crown-8 with 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone have been studied in methylene chloride by using spectroscopic methods. These crown ethers from 1:l molecular complexes with the acceptor. The magnitudes of association constants and thermodynamic parameters of complexation are indicative of cooperative interaction of oxygens with the acceptor.

Interaction of Gibberellic Acid and Indole-3-acetic Acid in the Growth of Excised Cuscuta Shoot Tips in Vitro1

Gibberellic acid (GA3) induced a marked elongation of 2.5-centimeter shoot tips of Cuscuta chinensis Lamk. cultured in vitro. In terms of the absolute amount of elongation, this growth may be the largest reported for an isolated plant system. The response to hormone was dependent on an exogenous carbohydrate supply. The hormone-stimulated growth was due to both cell division and cell elongation. The growth response progressively decreased if GA3 was given at increasingly later times after culturing, but the decreased growth response could be restored by the application of indole-3-acetic acid (IAA) to the apex. Explants deprived of GA3 gradually lost their ability to transport IAA basipetally, but this ability was also restored by auxin application. The observations are explained on the basis that: (a) the growth of Cuscuta shoot tip in vitro requires, at least, both an auxin and a gibberellin; and (b) in the absence of gibberellin the cultured shoot tip explants lose the ability to produce and/or transport auxin.

ESR study of metal ion-guanosine monophosphate interaction

The addition of guanosine 5-monophosphate (5′-GMP) to an aqueous solution of Mn2+ ions results in a decrease in ESR signal intensity and an increase in line-width of Mn2+ ions. This can be interpreted in terms of stepwise formation of outersphere and inner-sphere complexes as When Mg2+ is added to a mixture of Mn2+ and 5′-GMP, ESR signal intensity increases, presumably due to the replacement of Mn2+ by Mg2+ in the complex. From the variation of ESR signal intensity as a function of concentration of Mg2+, the product K1K2 for the magnesium complex i s calculated as 125 M−1. This difference in stability constants may indicate that both phosphate group and guanine base are involved in the formation of Mn2+-5′-GMP complex.

On a generalized dynamic model of bi-state social interaction processes

A non-linear model, construed as a generalized version of the models put forth earlier for the study of bi-state social interaction processes, is proposed in this study. The feasibility of deriving the dynamics of such processes is demonstrated by establishing equivalence between the non-linear model and a higher order linear model.

Optical and magnetic resonance studies of the interaction of metallo tetraphenylporphyrins with nitrobenzofuroxan

Metallo tetraphenylporphyrins form I : I molecular complexes with 4,6-dinitrobenzofuroxan. The molecular association is described in terms of T-n. interaction with porphyrins functioning as donors. The association constants and thermodynamic parameters have been evaluated using optical absorption and 'H nmr spectral methods. Based on the binding constants, the donor ability of various metalloporphyrins can be arranged in the following order: Pd(I1) > Co(I1) > Cu(I1) > Ni(I1) - VO(1V) - 2H > Zn(l1). Electron paramagnetic resonance studies of the complexes reveal that the IT-complexation results in changes in the electronic structure of the central metal ions which are reflected in the changes in the M-N 5 bonding. The dipolar contribution to the acceptor proton chemical shifts in the CoTPP complex has been partitioned from ring current contributions using the shifts observed in the ZnTPP complex. The shifts, along with the line broadening ratios observed for the CoTPP complex, are used to arrive at the possible solution structures of the complexes.

Mode of action of antitumour antibiotics: Spectrophotometric studies on the interaction of chromomycin A3 with DNA and chromatin of normal and neoplastic tissue

The binding of chromomycin A3, an antitumour antibiotic, to various DNA and chromatin isolated from mouse and rat liver, mouse fibrosarcoma and Yoshida ascites sarcoma cells was studied spectrophotometrically at 29°C in 10−2 M Tris-HCl buffer, pH 8.0, containing small amounts of MgCl2 (4.5 · 10−5−25 · 10−5 M). An isobestic point at 415 nm was observed when chromomycin A3 was gradually titrated with Image and its spectrum shifted towards higher wavelength. The rates and extent of these spectral changes were found to be dependent on the concentration of Mg2+. The change in absorbance at 440 nm was used to calculate apparent binding constant (Ka p M−1) and sites per nucleotide (n) from Scatchard plots for various DNA and chromatins. As expected, values of n for chromatin (0.06–0.10) were found to be lower than that found for corresponding DNA (0.10–0.15). Apparently no such correlation exists between binding constants (Ka p M−1 · 10−4) of DNA (6.4–11.2) and of chromatin (3.1–8.3), but Ka p M−1 of chromatin isolated from mouse fibrosarcoma and Yoshida ascites sarcoma are 1.5–3 times higher than that found for mouse and rat liver chromatin. These differences may be taken to indicate structural difference in nucleoprotein complexes caused by neoplasia. The relevance of this finding to tumour suppressive action of chromomycin A3 is discussed.

Molecular complexes of macrocyclic polyethers with 1, 3, 5-trinitrobenzene

The interaction of six macrocyclic polyethers with 1, 3, 5-trinitrobenzene has been studied by spectroscopic methods. The association constants have been evaluated by1HMR chemical shift method. There is evidence that major contribution to the interaction isvia n andπ electrons. The donor strengths of the polyethers have been evaluated.