Discovery of enzyme inhibitors through combinatorial chemistry

Summary This review serves to highlight the recent examples of combinatoric methodology as applied to the discovery and optimization of enzyme inhibitors. Early research efforts focused on the identification of polypeptides from libraries as inhibitors of proteases. As solution- and solid-phase chemistries gain in sophistication, libraries containing less peptidic structural motifs have been created. A recurring design stratagem relies on the synthesis of libraries incorporating pharmacophores with known affinity for the target enzyme. Screening of these structure-based libraries has led to the discovery of small-molecule inhibitors of both proteolytic and non-proteolytic enzymes alike. Two tables are provided listing the enzyme targeted libraries through 1996. A name, generic structure and size is given for each library citation, accompanied by the enzyme screen and the structure and potency of the most active library member.     

基于微燃机的空气湿化循环构建与分析

基于同一微燃机,构建了注水回热(RWI)、HAT、部分空气湿化(PHAT)、压气机入口喷雾冷却的HAT(AHAT)循环模型,对各循环的性能进行了模拟分析并对比了效率和比功.结果表明,在可比条件下,空气湿化循环功率和效率较回热循环分别提高40%以上和5个百分点左右.研究结果为微燃机改造为空气湿化循环提供了依据和理论指导.     

Thermodynamic and kinetic analysis of the reaction between biological catecholamines and chlorinated methylperoxy radicals

The antiradical potency of catecholamines (dopamine, epinephrine, norepinephrine, L-DOPA), metabolites of dopamine (homovanillic acid, 3-methoxytyramine and 3,4-dihydroxyphenylacetic acid) and catechol towards substituted methylperoxy radicals is investigated. The thermodynamic parameters, together with the kinetic approach, are used to determine the most probable mechanism of action. The natural bond orbital and quantum theory of atoms in molecules are utilised to explain the highest reactivity of trichloromethylperoxy radical. The preferred mechanism is dependent both on the thermodynamic and kinetic parameters . The number of chlorine atoms on radical, the presence of intra-molecular hydrogen bond and number of hydroxy groups attached to the aromatic ring significantly influence the mechanism. The results suggest that sequential proton loss electron transfer (SPLET) is the most probable for reaction with methylperoxy and hydrogen atom transfer (HAT) for reaction with trichloromethylperoxy radicals, with a gradual transition between SPLET and HAT for other two radicals. Due to the significant deprotonation of molecules containing the carboxyl group, the respective anions are also investigated. The HAT and SPLET mechanisms are highly competitive in reaction with MP radical, while the dominant mechanism towards chlorinated radicals is HAT. The reactions in methanol and benzene are also discussed.     

Composite of discotic liquid crystal and gold nanoparticles: A comperative band gap study

Nanocomposites of discotic liquid crystal namely 2, 3, 6, 7, 10, 11-hexabutyloxytryphenylene (HAT4) in existence of variable concentration of gold nanoparticles (GNPs) have been studied at room temperature and zero pressure. The absorption spectra of nanocomposites are captured by a Shimadzu UV–VIS Spectrophotometer, model UV-1800, in the wavelength range 900–200?nm. In this paper using the Tauc’s relation, the absorption spectra fitting method was applied to estimate the optical band gap. Nanocomposites are prepared by mixing of GNPs with four concentrations in pure HAT4 viz. 0.2, 0.6, 1.2 and 3?wt%. From the investigation of absorption spectra, it has been observed that with the enhance of GNPs concentration in pure HAT4 band gap has decreased for lower concentrations but for higher concentration (3?wt%) it increases.     

HAT HMBC: a hybrid of H2BC and HMBC overcoming shortcomings of both

A new 2D NMR experiment, HAT HMBC, that is a hybrid of H2BC and HMBC aims at establishing two-bond correlations absent in H2BC spectra because of vanishing (3)J(HH) coupling constants. The basic idea is to create an additional pi phase difference in the multiplet structure in HMBC peaks with respect to the (n+1)J(HH) coupling constant between the proton(s) attached to a (13)C and a (1)H separated by n bonds. Thus HMBC peaks associated with small J(HH) will be the most attenuated in a HAT HMBC spectrum in comparison to a regular HMBC spectrum, i.e. peaks associated with (n+1)J(HH) and (n)J(CH) will for n>2 usually be strongly attenuated. The HAT HMBC pulse sequences contain the same number of pulses as regular HMBC and are only a few milliseconds longer.     

Hydrogen abstraction from H‐donor substrates by the 6‐CF3‐benzotriazol‐N‐oxyl radical (TFNO)

The aminoxyl radical 6‐trifluoromethyl‐benzotriazol‐N‐oxyl (TFNO) has been generated from the parent hydroxylamine 6‐CF₃‐1‐hydroxy‐benzotriazole (TFBT) by one‐electron oxidation with a Ce^IV salt and characterized by spectrophotometry and cyclic voltammetry (CV). Rate constants of H‐abstraction (k_H) by TFNO from a number of H‐donor benzylic substrates have been determined spectrophotometrically in MeCN solution at 25 °C. A radical H‐atom transfer (HAT) route of oxidation is substantiated for TFNO by several pieces of evidence. The kinetic data also testify the relevance of stereoelectronic effects upon the HAT reactivity of TFNO. Copyright © 2010 John Wiley & Sons, Ltd.     

Interrogating the druggable genome with structural informatics

Summary Structural genomics projects are producing protein structure data at an unprecedented rate. In this paper, we present the Target Informatics Platform (TIP), a novel structural informatics approach for amplifying the rapidly expanding body of experimental protein structure information to enhance the discovery and optimization of small molecule protein modulators on a genomic scale. In TIP, existing experimental structure information is augmented using a homology modeling approach, and binding sites across multiple target families are compared using a clique detection algorithm. We report here a detailed analysis of the structural coverage for the set of druggable human targets, highlighting drug target families where the level of structural knowledge is currently quite high, as well as those areas where structural knowledge is sparse. Furthermore, we demonstrate the utility of TIP's intra- and inter-family binding site similarity analysis using a series of retrospective case studies. Our analysis underscores the utility of a structural informatics infrastructure for extracting drug discovery-relevant information from structural data, aiding researchers in the identification of lead discovery and optimization opportunities as well as potential “off-target” liabilities.     

Performance evaluation of N × 40 Gbps CS-RZ and DCS-RZ modulated signals transmitted over single mode fiber based on non-ideal LiNbO<Subscript>3</Subscript> Mach-Zehnder modulators

We investigate the transmission performance of N × 40 Gbps carrier-suppressed return-to-zero (CS-RZ) and duobinary CS-RZ (DCS-RZ) modulated wavelength division multiplexed (WDM) signals over the standard single-mode fiber (SSMF) based on non-ideal Mach-Zehnder (MZ) modulators through numerical simulations. In addition to that, the impact on receiver margin related to the residual chirp due to an asymmetry ratio of modulators as well as the effect of the applied chirp of modulators has been studied. As the asymmetry ratio of modulators is increased, dispersion penalties are increased asymmetrically at around the zero dispersion wavelength for the CS-RZ format. The DCS-RZ modulation format has a symmetric behavior due to different characteristics of the residual chirp of modulators. The receiver margin for the DCS-RZ modulation format is larger than the CS-RZ modulation format above the asymmetry ratio of 0.82 of modulators (extinction ratio of 20 dB) with the optimal Δλ_DCF. By controlling the negative/positive applied chirp of the first/second modulator, dispersion penalties can be reduced for both the CS-RZ and DCS-RZ formats. In the DCS-RZ format compared to the CS-RZ format, the effect of the applied chirp of the first modulator is more dominant than that of the second modulator. The simulation results show that the receiver margin is limited by the asymmetry ratio of modulators as well as a deviated wavelength from the zero dispersion wavelength of dispersion compensating fibers (DCF) in order to be fully post-compensated. Dispersion penalties can be reduced with appropriate chirp parameters of two non-ideal modulators.     

HAT循环的模化与热力学评价

ＨＡＴ循环的模化与热力学评价肖云汉，蔡睿贤，林汝谋（中国科学院工程热物理研究所北京１０００８０）关键词ＨＡＴ循环，系统优化，集成１引言ＨＡＴ循环，以其突出的高效率、低费用和低ＮＯｘ污染以及许多其它的优点表现为一种新型的先进的发电系统，被列入美国先进透...     

HAT循环的系统优化

ＨＡＴ循环的系统优化肖云汉，林汝谋，蔡睿贤（中国科学院工程热物理所北京１０００８０）关键词：ＨＡＴ循环，系统优化一、前言ＨＡＴ循环采用两相、多组份的混合工质，利用现有成熟的部件技术，以低造价的简单系统实现高效率、高比功、低污染和良好的变工况性能，引起...     

基于微燃机的HAT循环变工况性能分析

基于某微燃机构建了HAT循环,研究了其在功率下降(ISO条件)、环境温度变化时的变工况性能,并与简单循环、回热循环和RWI(注水回热)循环的设计工况、变工况性能进行了对比。结果表明, HNI、循环和RWI循环的变工况性能相似且好于简单循环和回热循环。其中,空气湿化程度的调整对于HAT循环变工况性能的稳定性起重要作用。但由于没有设置中冷器,且微燃机循环中可资利用的(火用)较少,HAT循环设计工况和变工况性能相对于其它循环的优势没有得到充分体现。     

HPLC-MS/MS检测人血浆中的茴三硫代谢物对羟基茴三硫及生物等效性

用HPLC-MS/MS内标法定量测定人血浆中茴三硫代谢物对羟基茴三硫的浓度。采用InertsilODS-3色谱柱(150mm×2.1mm,3μm),流动相为甲醇;水=85:15(V/V),采用多反应监测(MRM)模式。对羟基茴三硫在0.452—603.2ng/mL浓度范围内具有良好的线性关系,日内、日间相对标准偏差(RSD)和准确度误差(RE)均小于12%。该方法灵敏、准确、快速,已用于茴三硫片体内药动学的研究。     

偏置M-Z调制器构建2-bits电光模数转换相位编码方法的分析与模拟

为了降低电光相位编码器功率消耗和解决内部M Z调制器一致性要求高的问题,利用2个偏置M Z调制器构成了用于电光模数转换的2 bits电光相位编码器。理论分析了偏置M Z调制器实现2 bits电光相位编码的方法、特点和性能。仿真结果验证了采用偏置M Z调制器构成的2 bits相位编码方法可行性,并实现了对1 GHz模拟电信号的采样速率12 GSa/s模数转换。分析和仿真结果表明,采用该方法对调制器一致性要求低,对输入信号功率要求低于0.32 W。分析结果表明,调制器直流漂移不影响最低位量化结果,引起最高位量化结果的判决模糊低于3.8%。     

Intersubband electro-optic modulators for near and mid infrared applications

Optical transitions between conduction subbands of asymmetrical quantum-well structures can produce large second-order optical nonlinearities. In particular, it is possible to engineer asymmetrical quantum-well structures to have very large electro-optic (EO) coefficients. In this paper we study three alternative approaches to design and fabricate intersubband EO modulators, i.e. the Stark modulator, the quantum-interference (QI) modulator, and the carrier-density (CD) modulator. We show that near a given resonance the Stark modulator has the largest EO coefficient. However, the linear intersubband absorption limits the usability of this modulator to a very short device length. Far from resonance we found that the CD and the QI modulators are more efficient. Furthermore, we found that these modulators can be utilized for near-infrared modulation in the 1.3–1.5 μm spectral range. These modulators are almost unaffected by the linear intersubband absorption so that their efficiency can be very high. We present preliminary experimental results that demonstrate the operation of the QI modulator.     

Experimental demonstration of microring quadrature phase-shift keying modulators

Advanced optical modulation formats are a key technology to increase the capacity of optical communication networks. Mach-Zehnder modulators are typically used to generate various modulation formats. Here, we report the first experimental demonstration of quadrature phase-shift keying (QPSK) modulation using compact microring modulators. Generation of 20 Gb/s QPSK signals is demonstrated with 30 μm radius silicon ring modulators with drive voltages of ~6 V. These compact QPSK modulators may be used in miniature optical transponders for high-capacity optical data links.     

The effect of temporal asymmetry on amplitude modulation detection using pure-tone carriers (L)

The effect of temporal asymmetry on amplitude modulation detection was studied using sawtooth modulators with rising (ramped) or falling (damped) temporal envelopes within each period of modulation. For pure-tone carriers, damped modulation was more detectable than ramped modulation for a 5-kHz carrier (by a threshold difference of 3.2 dB on average) but not for a 1-kHz carrier. The threshold difference obtained at 5 kHz between the ramped and damped modulators was consistent across modulation rates (8-128 Hz). This carrier frequency dependence suggests that the effect of temporally asymmetry on modulation detection originates from envelope-based, within-channel mechanisms.     

Optically-addressed spatial light modulators

The performance characteristics of three unique optically-addressed spatial light modulators (SLMs) have been experimentally investigated. The measured parameters include resolution, visibility, imaging response time, and write light sensitivity. The modulators investigated include two relatively new technologies, the ferroelectric liquid crystal (FLC) SLM from the University of Colorado-Boulder and the amorphous silicon photoconductive twisted nematic liquid crystal SLM from GEC-Marconi Research, and a well-established industry benchmark, the Hughes Liquid Crystal Light Valve (LCLV).     

基于石墨烯的太赫兹器件研究进展

石墨烯是一种零带隙二维的半导体材料, 具有极高的载流子迁移率, 优异的机械、电学、热学和光学等性能. 在太赫兹辐射源、调制器和探测器件的研究中, 石墨烯材料具有独特的优势. 本文以石墨烯材料在太赫兹辐射源、调制器以及探测器等器件方面的应用为主, 综述了石墨烯太赫兹器件的最新研究进展.     

Nonlinear effects in blue-shift waveguide EAM's

To exploit the vast bandwidth of optical communication systems for high bit-rate long-haul transmission, external modulators show a better system performance than directly modulated lasers. One of the main advantages of electroabsorption modulators (EAM's) compared with Mach–Zehnder modulators is the possibility to integrate the modulator with a laser having the same active layer. This reduces processing complexity and system costs. Usually the quantum confined Stark effect results in a red shift of the absorption, which leads to a small gain due to a detuned operation of the integrated laser. In contrast, blue shift structures have been proposed for these integrated devices as they show both good laser and modulator properties. These structures suffer from the drawback that saturation effects may occur for higher optical power as these devices absorb the optical power at low applied bias. The aim of this paper is to investigate the influence of nonlinear saturation effects like carrier accumulation, Burnstein–Moss-effect and carrier screening.     

Dynamic modulation in graphene-integrated silicon photonic crystal nanocavity

Silicon-based electro-optic modulators are the key devices in integrated optoelectronics. Integration of the graphene layer and the photonic crystal(PC) cavity is a promising way of achieving compact modulators with high efficiency. In this paper, a high-quality(Q) acceptor-type PC nanocavity is employed to integrate with a single-layer graphene for realizing strong modulation. Through tuning the chemical potential of graphene, a large wavelength shift of 2.62 nm and a Q factor modulation of larger than 5 are achieved. A modulation depth(12.8 dB) of the reflection spectrum is also obtained.Moreover, the optimized PC nanocavity has a large free spectral range of 131.59 nm, which can effectively enhance the flexibility of the modulator. It shows that the proposed graphene-based PC nanocavity is a potential candidate for compact,high-contrast, and low-power absorptive modulators in integrated silicon chips.