Molecular characteristics of the inhibition of human neutrophil elastase by nonsteroidal antiinflammatory drugs

Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-phi radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.     

Evaluation of Poisson solvation models using a hybrid explicit/implicit solvent method

Implicit solvent methods have become popular tools in the field of protein dynamics simulations, yet evaluation of their validity has been primarily limited to comparisons with experimental and theoretical data for small molecules. In this paper, we use a recently developed hybrid explicit/implicit solvent methodology to evaluate the accuracy of several Poisson-based implicit solvent models. Specifically, we focus on the calculation of electrostatic solvation free energies of various fixed conformations for two proteins. We show that, among various dielectric boundary definitions, the Lee-Richards molecular surface has the best agreement with hybrid solvent results. Furthermore, certain modifications of the molecular surface Poisson protocol provide varied results. For instance, simple modifications of atomic radii on charged residues generally improve absolute errors but do not significantly reduce relative errors among conformations. On the other hand, using a water-probe radius of 1.0 A, as opposed to the standard value of 1.4 A, to generate the molecular surface, moderately improves both absolute and relative results.     

Total internal reflection-based biochip utilizing a polymer-filled cavity with a micromirror sidewall

A total internal reflection (TIR)-based biochip utilizing a polymer-filled cavity with a micromirror sidewall has been designed and fabricated. The implementation of the micromirror sidewall cavity facilitates precise alignment of the excitation light beam into the system. The incident angle of illumination can be easily modified by selecting polymers of different indices of refraction while optical losses are minimized. The design enables the hybrid, vertical integration of a laser diode and a CCD camera, resulting in a compact optical system. Brownian motion of fluorescent microspheres and real-time photobleaching of rhodamine 6G molecules is demonstrated. The proposed TIR-based chip simplifies current TIR optical configurations and could potentially be used as an optical-microfluidic platform for an integrated lab-on-a-chip microsystem.     

Ab initio studies of the allylic hydroxylation: DFT calculation on the reaction of 2-methyl-2-butene with selenium dioxide

The mechanism of the allylic oxidation of 2-methyl-2-butene with selenium dioxide has been investigated by ab initio quantum mechanics. Transition states for two major steps (an ene reaction and a [2,3]-sigmatropic rearrangement) of this reaction have been optimized by the B3LYP/6-311+G(d,p) method. A comparison of the energies of the transition states shows that the anti-endo and syn-endo approaches are the efficient routes in the ene reaction and the methyl (C4) group is sited in a pseudo-equatorial environment in cyclic transition states during the [2,3]-rearrangement. Calculations also show the kind of the terminal alkyl (C4) substituents may control (E)-selectivity in the formation of the allylic alcohols.     

Numerical computations of integrals over paths on Riemann surfaces of genusN

This paper is a continuation of work by Forest and Lee [1,2]. In [1,2] it was proved that the function theory of periodic soliton solutions occurs on the Riemann surfaces ? of genusN, where the integrals over paths on ? play the most fundamental role. In this paper a numerical method is developed to evaluate these integrals. Predisely, the aim is to develop a computational code for integrals of the form $$\int\limits_\gamma {f(z)\frac{{dz}}{{R(z)}}, or} \int\limits_\gamma {f(z)R(z)dz,} $$ wheref(z) is any single-valued analytic function on the complex planeC, andR(z) is a two-valued function onC of the form $$R^2 (z) = \prod\limits_{k = 1}^{2N + \delta } {(z - z_0 (k)), \delta = 0 or 1,} $$ where {z ₀(k),1≤k≤2N+δ} are distinct complex numbers which play the role of the branch points of the Riemann surface ? = {(z, R(z))} of genusN?1+δ. The integral path γ is continuous on ?. The numerical code is developed in “Mathematica” [3].