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Jianhua Shen

Publications and source records attributed to Jianhua Shen.

At least 19 recordsLinked to original sources
PubMed2007

Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay.

Potassium ion (K+) channels are attractive targets for drug discovery because of the essential roles played in biological systems. However, high-throughput screening (HTS) cannot be used to screen K+ channel blockers. To overcome this disadvantage of HTS, we have developed a virtual screening approach for discovering novel blockers of K+ channels. On the basis of a three-dimensional model of the eukaryotic K+ channels, molecular docking-based virtual screening was employed to search the chemical database MDL Available Chemicals Directory (ACD). Compounds were ranked according to their relative binding energy, favorable shape complementarity, and potential to form hydrogen bonds with the outer mouth of the K+ channel model. Twenty candidate compounds selected from the virtual screening were examined using the whole-cell voltage-clamp recording in rat dissociated hippocampal neurons. Among them, six compounds (5, 6, 8, 18-20) potently blocked both the delayed rectifier (IK) and fast transient K+ currents (IA). When applied externally, these six compounds preferentially blocked IK with potencies 2- to 500-fold higher than that of tetraethylammonium chloride. Intracellular application of the six compounds had no effect on both K+ currents. In addition, the interaction models and binding free energy calculations demonstrated that hydrophobic interaction and solvent effects play important roles in the inhibitory activities of these compounds. The results demonstrated that structure-based computer screening strategy could be used to identify novel, structurally diverse compounds targeting the pore binding pocket of the outer mouth of voltage-gated K+ channels. This study provides an alternative way of finding new blockers of voltage-gated K+ channels, while the techniques for high-throughput screening of K+ channel drugs remain in development.

Animals↗
PubMed2006

Discovering severe acute respiratory syndrome coronavirus 3CL protease inhibitors: virtual screening, surface plasmon resonance, and fluorescence resonance energy transfer assays.

An integrated system has been developed for discovering potent inhibitors of severe acute respiratory syndrome coronavirus 3C-like protease (SARS-CoV 3CL(pro)) by virtual screening correlating with surface plasmon resonance (SPR) and fluorescence resonance energy transfer (FRET) technologies-based assays. The authors screened 81,287 small molecular compounds against SPECS database by virtual screening; 256 compounds were subsequently selected for biological evaluation. Through SPR technology-based assay, 52 from these 256 compounds were discovered to show binding to SARS-CoV 3CL(pro). The enzymatic inhibition activities of these 52 SARS-CoV 3CL(pro) binders were further applied to FRET-based assay, and IC(50) values were determined. Based on this integrated assay platform, 8 new SARS-CoV 3CL(pro) inhibitors were discovered. The fact that the obtained IC(50) values for the inhibitors are in good accordance with the discovered dissociation equilibrium constants (K(D)s) assayed by SPR implied the reliability of this platform. Our current work is hoped to supply a powerful approach in the discovery of potent SARS-CoV 3CL(pro) inhibitors, and the determined inhibitors could be used as possible lead compounds for further research.

Binding Sites↗
PubMed2006

Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study.

A large series of pharmacological agents, distinct from the typical competitive antagonists, block in a noncompetitive manner the permeability response of the nicotinic acetylcholine receptor (nAChR) to the neurotransmitter acetylcholine. Taking the neuroleptic chlorpromazine (CPZ) as an example of such agents, the blocking mechanism of noncompetitive inhibitors to the ion channel pore of the nAChR has been explored at the atomic level using both conventional and steered molecular dynamics (MD) simulations. Repeated steered MD simulations have permitted calculation of the free energy (approximately 36 kJ/mol) of CPZ binding and identification of the optimal site in the region of the serine and leucine rings, at approximately 4 A from the pore entrance. Coulomb and the Lennard-Jones interactions between CPZ and the ion channel as well as the conformational fluctuations of CPZ were examined to assess the contribution of each to the binding of CPZ to the nAChR. The MD simulations disclose a dynamic interaction of CPZ binding to the nAChR ionic channel. The cationic ammonium head of CPZ forms strong hydrogen bonds with Glu262 (alpha), Asp268 (beta), Glu272 (beta), Ser276 (beta), Glu280 (delta), Gln271 (gamma), Glu275 (gamma), and Asn279 (gamma) nAChR residues. Finally, the conventional MD simulation of CPZ at its identified binding site demonstrates that the binding of CPZ not only blocks ion transport through the channel but also markedly inhibits the conformational transitions of the channel, necessary for nAChR to carry out its biological function.

Acetylcholine↗
PubMed2006

Structure-based de novo design, synthesis, and biological evaluation of the indole-based PPARgamma ligands (I).

MCSS and LeapFrog, two de novo drug design programs, were used for the novel indole-based PPARgamma ligands' study. The designed compounds were synthesized and tested for the PPARgamma protein binding activities in vitro. Out of the compounds that were synthesized, two molecules (compounds 14d and 7d) possessed potent PPARgamma protein binding activity close to rosiglitazone in vitro.

Algorithms↗
PubMed2006

Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues.

To find useful information for discovering dual functional inhibitors against both wild type (WT) and K103N mutant reverse transcriptases (RTs) of HIV-1, molecular docking and 3D-QSAR approaches were applied to a set of twenty-five 4,1-benzoxazepinone analogues of efavirenz (SUSTIVA), some of them are active against the two RTs. 3D-QSAR models were constructed, based on their binding conformations determined by molecular docking, with r(2)(cv) values ranging from 0.656 to 0.834 for CoMFA and CoMSIA, respectively. The models were then validated to be highly predictive and extrapolative by inhibitors in two test sets with different molecular skeletons. Furthermore, CoMFA models were found to be well matched with the binding sites of both WT and K103N RTs. Finally, a reasonable pharmacophore model of 4,1-benzoxazepinones were established. The application of the model not only successfully differentiated the experimentally determined inhibitors from non-inhibitors, but also discovered two potent inhibitors from the compound database SPECS. On the basis of both the 3D-QSAR and pharmacophore models, new clues for discovering and designing potent dual functional drug leads against HIV-1 were proposed: (i) adopting positively charged aliphatic group at the cis-substituent of C3; (ii) reducing the electronic density at the position of O4; (iii) positioning a small branched aliphatic group at position of C5; (iv) using the negatively charged bulky substituents at position of C7.

Drug Design↗
PubMed2006

TarFisDock: a web server for identifying drug targets with docking approach.

TarFisDock is a web-based tool for automating the procedure of searching for small molecule-protein interactions over a large repertoire of protein structures. It offers PDTD (potential drug target database), a target database containing 698 protein structures covering 15 therapeutic areas and a reverse ligand-protein docking program. In contrast to conventional ligand-protein docking, reverse ligand-protein docking aims to seek potential protein targets by screening an appropriate protein database. The input file of this web server is the small molecule to be tested, in standard mol2 format; TarFisDock then searches for possible binding proteins for the given small molecule by use of a docking approach. The ligand-protein interaction energy terms of the program DOCK are adopted for ranking the proteins. To test the reliability of the TarFisDock server, we searched the PDTD for putative binding proteins for vitamin E and 4H-tamoxifen. The top 2 and 10% candidates of vitamin E binding proteins identified by TarFisDock respectively cover 30 and 50% of reported targets verified or implicated by experiments; and 30 and 50% of experimentally confirmed targets for 4H-tamoxifen appear amongst the top 2 and 5% of the TarFisDock predicted candidates, respectively. Therefore, TarFisDock may be a useful tool for target identification, mechanism study of old drugs and probes discovered from natural products. TarFisDock and PDTD are available at http://www.dddc.ac.cn/tarfisdock/.

Databases, Protein↗
PubMed2006

Sleepiness is not the inverse of alertness: evidence from four sleep disorder patient groups.

The constructs "sleepiness" and "alertness" are often assumed to be reciprocal states of consciousness. This distinction is of increasing concern in relation to psychomotor performance tasks such as driving. We developed two separate subjective scales of alertness to complement existing sleepiness scales. Subjective sleepiness and alertness were compared in four groups of sleep-disordered patients. In a 175-patient cohort [25 narcoleptics and 50 each with sleep apnea, insomnia and periodic leg movement disorder (PLMD)], the Epworth Sleepiness Scale (ESS) was used to measure sleepiness while the Toronto Hospital Alertness Test (THAT) and ZOGIM Alertness Scale (ZOGIM-A) were used to measure alertness. Significant differences existed for sleepiness scores, with narcoleptics scoring highest on the ESS, followed by sleep apnea, with similar ESS scores for insomnia and PLMD. By contrast, alertness scores on both the THAT and ZOGIM-A did not differ significantly between the four groups. Sleepiness scores show a correlation of close to nil to alertness scores for the combined sleep disorder patient cohort, with the exception of insomnia patients, where a modest but significant inverse relationship was noted between sleepiness and alertness. Subjective states of impaired alertness and excessive sleepiness are independent constructs in the evaluation of sleep-disordered patients. The specific primary sleep disorder diagnosis may play a relevant role in mitigating this interrelationship.

Adult↗
PubMed2006

How does ammonium dynamically interact with benzene in aqueous media? A first principle study using the Car-Parrinello molecular dynamics method.

The Car-Parrinello molecular dynamics (CPMD) method was used to study the dynamic characteristics of the cation-pi interaction between ammonium and benzene in gaseous and aqueous media. The results obtained from the CPMD calculation on the cation-pi complex in the gaseous state were very similar to those calculated from the Gaussian98 program with DFT and MP2 algorithms, demonstrating that CPMD is a valid approach for studying this system. Unlike the interaction in the gaseous state, our 12-ps CPMD simulation showed that the geometry of the complex in aqueous solution changes frequently in terms of the interaction angles and distances. Furthermore, the simulation revealed that the ammonium is constantly oscillating above the benzene plane in an aqueous environment and interacts with benzene mostly through three of its hydrogen atoms. In contrast, the interaction of the cation with the aromatic molecule in the gaseous state involves two hydrogen atoms. In addition, the free energy profile in aqueous solution was studied using constrained CPMD simulations, resulting in a calculated binding free energy of -5.75 kcal/mol at an optimum interaction distance of approximately 3.25 A, indicating that the cation-pi interaction between ammonium and benzene is stable even in aqueous solution. Thus, this CPMD study suggested that the cation-pi interaction between an ammonium (group) and an aromatic structure could take place even on surfaces of protein or nucleic acids in solution.

Benzene↗
PubMed2006

Psychomotor disturbance in depression: assessment using a driving simulator paradigm.

BACKGROUND: Psychomotor disturbance is an essential feature of Major Depressive Disorder (MDD) and has been associated with impaired functioning on cognitively demanding tasks. Given the psychomotor demands required to navigate a motor vehicle and the disastrous effects of motor vehicles accidents, patients with MDD present a population of clinical interest. The goal of this investigation was to examine the association between MDD and driving ability assessed within a simulated driving paradigm. METHODS: 18 outpatients currently meeting diagnostic criteria for MDD and 29 control participants completed four 30-min simulated driving trials at 10:00 am, 12:00 pm, 2:00 pm, and 4:00 pm. Participants also completed the Beck Depression Inventory (BDI) to assess for depression severity and the Epworth Sleepiness Scale (ESS) to assess for everyday sleepiness. RESULTS: After controlling for age and sleepiness, the depressed sample exhibited slower steering reaction times across trials (p<.05) and an increased number of crashes across trials (p<.05) when compared to controls. These differences were characterized by a medium effect size. No significant time-of-day effects were found. LIMITATIONS: MDD patients were free of anti-depressant medication and findings may not generalize to medicated populations. Also, a rural highway driving route was used which may not generalize well to urban driving settings. CONCLUSIONS: Patients with untreated MDD demonstrate impaired simulated driving performance. Further research into whether these findings translate into on-the-road impairment is important for public health and safety.

Accidents, Traffic↗
PubMed2006

Structural insights into the effect of isonucleosides on B-DNA duplexes using molecular-dynamics simulations.

Some structural insights into the conformations of the isonucleosides containing duplexes have been provided. Unrestrained molecular-dynamics simulations on 18-mer duplexes with isonucleosides incorporated at the 3'-end or in the center of one strand have been carried out with explicit solvent under periodic boundary conditions using the AMBER force field and the particle mesh Ewald method. The Watson-Crick hydrogen-bonding patterns of the duplexes studied remained intact throughout the simulation. For the modified duplexes, the changes observed in the inter-base pair parameters and backbone torsional angles were primarily localized at the isonucleoside-inserted area. All five structures studied remained in the B-form family. The decreased stacking abilities indicated by the large changes in inter-base pair parameters and the large changes in backbones made the modified duplexes show a minor thermal destabilization in comparison with native DNA. The MM_PBSA method for estimating binding free energies on two complementary strands was used. The results showed that the binding free energies of isonucleoside-incorporated DNA duplexes were lower than the native DNA duplex, which is in good agreement with experimental observations.

Computer Simulation↗
PubMed2006

Fatigue and shift work.

Shift work is a ubiquitous phenomenon and its adverse effects on workers' physical and mental health have been documented. In the sleep literature, differentiating between the symptoms of fatigue and sleepiness, and developing appropriate objective and subjective measures, have become very important endeavors. From such research, fatigue and sleepiness have been shown to be distinct and independent phenomena. However, it is not known whether shift work differentially affects fatigue and sleepiness. In an attempt to answer this question, 489 workers from a major Ontario employer completed a series of subjective, self-report questionnaires, including the Fatigue Severity Scale (FSS) and the Epworth Sleepiness Scale. Workers were separated into four groups based on the frequency with which they are engaged in shift work (never, fewer than four times per month, 1-2 days per week, 3 days or more per week). The frequency of shift work was found to have a significant effect on subjective fatigue, but not on subjective sleepiness. Compared with the subjects who never had a shift schedule, those who worked in a shift for 3 days or more had significantly higher mean score of the FSS. In agreement with previous results, a low correlation was found between workers' subjective fatigue and sleepiness scores, providing further support for the concept of fatigue and sleepiness as distinct and independent phenomena. Future research should address the possibility of using the FSS as an indicator when the frequency of shift work has become high enough to adversely affect work performance or cause health problems.

Adult↗
PubMed2006

Polysomnographic and symptomatological analyses of major depressive disorder patients treated with mirtazapine.

OBJECTIVE: This study aimed to characterize the effects of mirtazapine on polysomnographic sleep, especially slow wave sleep (SWS) and rapid eye movement (REM) sleep, as well as its effects on clinical symptoms in patients with major depressive disorder (MDD). METHOD: Sixteen MDD patients were treated with mirtazapine 30 mg taken 30 minutes before bedtime. Polysomnographic and subjective sleep, as well as other clinical data, were collected at baseline and on Days or Nights 2, 9, 16, 30, and 58 during treatment. We used repeated measures analysis of variance, including pairwise comparison, to analyze data statistically. RESULTS: Mirtazapine administration increased total SWS and the SWS in the first sleep cycle, but not SWS in the second sleep cycle. The medication increased REM latency and the duration of the first REM episode; it also decreased the number of REM episodes. Simultaneously, mirtazapine significantly reduced wake-after-sleep onset and scores on the Athens Insomnia Scale. After patients took the medication, scores on the Hamilton Depression Rating Scale-17 (HDRS-17) decreased rapidly and continuously. The changes on the Beck Depression Inventory-II were consistent with those on the HDRS-17. The medication has a tendency to increase weight. CONCLUSIONS: Mirtazapine significantly improved sleep quality, reversed sleep markers of depression, and reduced depressive symptoms in this group of MDD patients.

Adult↗
PubMed2006

Use of an alumina-on-alumina bearing system in total hip arthroplasty for osteonecrosis of the hip.

BACKGROUND: The results of total hip arthroplasty in patients with osteonecrosis of the femoral head are not always optimal. The use of alumina-on-alumina interfaces in young and active patients may decrease wear and lower the rate of aseptic loosening of the implant and appears to be an attractive alternative to the use of conventional cobalt-chromium-on-polyethylene bearings. The purpose of this study was to evaluate the safety and efficacy of the alumina-on-alumina bearing in patients with osteonecrosis and to compare this group of patients to a group of similarly treated patients with osteoarthritis and a group of patients who received conventional cobalt-chromium-on-polyethylene bearings. METHODS: Patients were selected from a United States Investigational Device Exemption multicenter prospective randomized clinical study that was initiated in 1996. Seventy patients with osteonecrosis of the femoral head (seventy-nine hips) received a cementless alumina-on-alumina bearing system and were directly matched to seventy-six patients with osteoarthritis of the hip (seventy-nine hips) who were managed with the same implant. Both groups were compared with twenty-five patients (twenty-six hips) with osteonecrosis and twenty-five patients (twenty-six hips) with osteoarthritis who were managed with a cementless cobalt-chromium-on-polyethylene bearing system. All patients received a cementless hydroxyapatite-coated femoral stem and were followed both clinically and radiographically. RESULTS: The clinical outcomes for alumina-on-alumina bearings were similar for both osteonecrotic and osteoarthritic hips. The seven-year survival probability was 95.5% for the osteonecrotic hips and 89.4% for the osteoarthritic hips in the alumina-on-alumina bearing group and 92.3% for the osteonecrotic hips and 92.9% for the osteoarthritic hips in the cobalt-chromium-on-polyethylene bearing group. At the time of the most recent follow-up, the mean Harris hip score was 96 points for both the osteonecrotic and the osteoarthritic hips in the alumina-on-alumina group and 96 points for the osteonecrotic hips and 97 points for the osteoarthritic hips in the cobalt-chromium-on-polyethylene bearing group. CONCLUSIONS: The results of the use of alumina-on-alumina and cobalt-chromium-on-polyethylene bearings in cementless standard total hip implants in patients with osteonecrosis and osteoarthritis were comparable. The low revision rate for the alumina-on-alumina bearing is encouraging and offers a promising option for younger, more active patients who have this challenging disease. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions to Authors on jbjs.org for a complete description of levels of evidence.

Adult↗
PubMed2006

An overall picture of SARS coronavirus (SARS-CoV) genome-encoded major proteins: structures, functions and drug development.

A severe atypical pneumonia designated as severe acute respiratory syndrome (SARS) by The World Health Organization broke out in China and menaced to more than other 30 countries between the end of the year 2002 and June of the year 2003. A novel coronavirus called severe acute respiratory syndrome coronavirus (SARS-CoV) has been recently identified as the etiological agent responsible for the infectious SARS disease. Based on extensively scientific cooperation and almost two-year's studies, remarkable achievements have been made in the understanding of the phylogenetic property and the genome organization of SARS-CoV, as well as the detailed characters of the major proteins involved in SARS-CoV life cycle. In this review, we would like to summarize the substantial scientific progress that has been made towards the structural and functional aspects of SARS-CoV associated key proteins. The progress focused on the corresponding key proteins' structure-based drug and vaccine developments has been also highlighted. The concerted and cooperative response for the treatment of the SARS disease has been proved to be a triumph of global public health and provides a new paradigm for the detection and control of future emerging infectious disease threats.

Antiviral Agents↗
PubMed2006

Molecular dynamics of nicotinic acetylcholine receptor correlating biological functions.

The nicotinic acetylcholine receptor (nAChR) that mediates fast intercellular communication in response to neurotransmitters is a paradigm of ligand-gated ion channels. Molecular dynamics (MD) simulations are valuable in understanding membrane protein function at atomic level, providing useful clues for further experimental/theoretical studies. In this brief review, recent progress in MD simulations of the nAChR has been illustrated, mainly focusing on the latest simulation of the whole transmembrane domain of the receptor. On the basis of MD simulations, asymmetrical and asynchronous motions of five subunits were observed both in the ligand binding and transmembrane domains; a closed-to-open conformational shift of the gate was captured in different simulation systems; the contributions from the lipid molecules and other transmembrane segments rather than M2 to the gate switch as well as the conformational change of the whole channel were assessed; the dynamic behavior and related physical/chemical properties of the water molecules and cations within the ion channel were examined; and an experimentally comparable single-channel conductance and ion selectivity were obtained.

Kinetics↗
PubMed2005

Distinguishing sleepiness and fatigue: focus on definition and measurement.

Sleepiness and fatigue are two interrelated, but distinct phenomena; observed in a number of psychiatric, medical and primary sleep disorders. Despite their different implications in terms of diagnosis and treatment, these two terms are often used interchangeably, or merged under the more general lay term of 'tired'. Sleepiness is multidimensional and has many causes (multidetermined) and distinguished from fatigue by a presumed impairment of the normal arousal mechanism. Despite its ubiquity, no clear consensus exits as yet as to what constitutes sleepiness. Definitions of sleepiness, to date, are at best operational definitions, conceptualized so as to produce specific assessment instruments. As a result, while a number of subjective and objective measurement tools have been developed to measure sleepiness, each only captures a limited aspect of an otherwise heterogeneous entity. Fatigue is an equally complex phenomenon, its nature captured by a number of conceptualizations and definitions. Measures of fatigue have remained subjective, with a 'gold standard' for its measurement remaining elusive. Despite a high prevalence and high degree of morbidity, fatigue has remained a relatively under appreciated symptom, from both a clinical and research point of view.

Disorders of Excessive Somnolence↗
PubMed2005

Dynamic mechanism of E2020 binding to acetylcholinesterase: a steered molecular dynamics simulation.

The unbinding process of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine) leaving from the long active site gorge of Torpedo californica acetylcholinesterase (TcAChE) was studied by using steered molecular dynamics (SMD) simulations on a nanosecond scale with different velocities, and unbinding force profiles were obtained. Different from the unbinding of other AChE inhibitors, such as Huperzine A that undergoes the greatest barrier located at the bottleneck of the gorge, the major resistance preventing E2020 from leaving the gorge is from the peripheral anionic site where E2020 interacts intensively with several aromatic residues (e.g., Tyr70, Tyr121, and Trp279) through its benzene ring and forms a strong direct hydrogen bond and a water bridge with Ser286 via its O24. These interactions cause the largest rupture force, approximately 550 pN. It was found that the rotatable bonds of the piperidine ring to the benzene ring and dimethoxyindanone facilitate E2020 to pass the bottleneck through continuous conformation change by rotating those bonds to avoid serious conflict with Tyr121 and Phe330. The aromatic residues lining the gorge wall are the major components contributing to hydrophobic interactions between E2020 and TcAChE. Remarkably, these aromatic residues, acting in three groups as "sender" and "receiver", compose a "conveyer belt" for E2020 entering and leaving the TcAChE gorge.

Acetylcholinesterase↗