Preliminary report: rapid prototyping models for Dysplastic hip surgery

Rapid prototyping (RP) is a technology used to produce physical models. The RP application is applied in the medical field to build anatomy models from high resolution multiplanar data such as Computed tomography (CT). CT of a female patient diagnosed with hip dysplasia was obtained prior to surgery. Specific software was used to prepare the physical model of the patient and was produced using fused deposition machine. Pre fused deposition models (FDM) were given to the orthopaedic surgeon to plan for the dysplastic hip dysplasia. The patient was scanned again using CT after surgery and a post model was produced. The outcome of the surgery was seen clearly by viewing the post model. Orthopaedic surgeon commented on his experience of using the models for the hip dysplasia surgery. These models were found to be very useful for pre surgery planning, determining procedure, implant sizes, positioning, bone grafting which also reduced surgery time by forty percent and increased surgeon confidence as rehearsal prior to actual surgery was made possible. This paper provides an understanding of the benefits of using RP models in hip dysplasia surgery as a good way to enhance both orthopaedic surgeon skill and knowledge.     

AVCpred: an integrated web server for prediction and design of antiviral compounds

Viral infections constantly jeopardize the global public health due to lack of effective antiviral therapeutics. Therefore, there is an imperative need to speed up the drug discovery process to identify novel and efficient drug candidates. In this study, we have developed quantitative structure–activity relationship (QSAR)‐based models for predicting antiviral compounds (AVCs) against deadly viruses like human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), human herpesvirus (HHV) and 26 others using publicly available experimental data from the ChEMBL bioactivity database. Support vector machine (SVM) models achieved a maximum Pearson correlation coefficient of 0.72, 0.74, 0.66, 0.68, and 0.71 in regression mode and a maximum Matthew's correlation coefficient 0.91, 0.93, 0.70, 0.89, and 0.71, respectively, in classification mode during 10‐fold cross‐validation. Furthermore, similar performance was observed on the independent validation sets. We have integrated these models in the AVCpred web server, freely available at http://crdd.osdd.net/servers/avcpred . In addition, the datasets are provided in a searchable format. We hope this web server will assist researchers in the identification of potential antiviral agents. It would also save time and cost by prioritizing new drugs against viruses before their synthesis and experimental testing.     

Recent progress in multiple sequence alignment: a survey

The assembly of a multiple sequence alignment (MSA) has become one of the most common tasks when dealing with sequence analysis. Unfortunately, the wide range of available methods and the differences in the results given by these methods makes it hard for a non-specialist to decide which program is best suited for a given purpose. In this review we briefly describe existing techniques and expose the potential strengths and weaknesses of the most widely used multiple alignment packages.     

Software for rapid prototyping in the pharmaceutical and biotechnology industries

The automation of drug discovery methods continues to develop, especially techniques that process information, represent workflow and facilitate decision-making. The magnitude of data and the plethora of questions in pharmaceutical and biotechnology research give rise to the need for rapid prototyping software. This review describes the advantages and disadvantages of three solutions: Competitive Workflow, Taverna and Pipeline Pilot. Each of these systems processes large amounts of data, integrates diverse systems and assists novice programmers and human experts in critical decision-making steps.     

MCDB: A comprehensive curated mitotic catastrophe database for retrieval,protein sequence alignment,and target prediction

Mitotic catastrophe (MC) is a form of programmed cell death induced by mitotic process disorders, which is very important in tumor prevention, development, and drug resistance. Because rapidly increased data for MC is vigorously promoting the tumor-related biomedical and clinical study, it is urgent for us to develop a professional and comprehensive database to curate MC-related data. Mitotic Catastrophe Database (MCDB) consists of 1214 genes/proteins and 5014 compounds collected and organized from more than 8000 research articles. Also, MCDB defines the confidence level, classification criteria, and uniform naming rules for MC-related data, which greatly improves data reliability and retrieval convenience. Moreover, MCDB develops protein sequence alignment and target prediction functions. The former can be used to predict new potential MC-related genes and proteins, and the latter can facilitate the identification of potential target proteins of unknown MC-related compounds. In short, MCDB is such a proprietary, standard, and comprehensive database for MC-relate data that will facilitate the exploration of MC from chemists to biologists in the fields of medicinal chemistry, molecular biology, bioinformatics, oncology and so on. The MCDB is distributed on http://www.combio-lezhang.online/MCDB/index_html/.     

Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design.

As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC(50) = 0.10 microM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC(50) = 0.042 microM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex.     

Similarity based virtual screening: a tool for targeted library design

High throughput screening drug discovery utilizes large and expensive compound libraries. As an alternative, a smaller targeted library can be constructed with the aid of the 3D structure of the target molecule. We used the X-ray crystal structure of a protein homologous to the selected target in creation of a small focused library and evaluated inhibition potential of this library against Chlamydia pneumoniae, a common pathogen recently linked to atherosclerosis and risk of myocardial infarction.     

Ciguatera: a rapid procedure for extraction of ciguatoxin

A rapid procedure for extraction and partial purification of ciguatoxin has been achieved and compared to one of the routine methods. Fish from two species which provided extracts of differing purity by the routine method were used. From 8 g of raw flesh, 1.0 +/- 0.2 mg of a semi-purified extract of ciguatoxin of homogeneous quality was obtained within 1 hr, whatever the species or toxicity of the fish. The results were reproducible, making the procedure very promising.     

Prediction of metabolism by cytochrome P450 2C9: alignment and docking studies of a validated database of substrates

A validated database of 70 molecules known to undergo biotransformation by CYP2C9 was collated. The molecular alignment program ROCS was used with the query molecule flurbiprofen as a basis for predicting the correct active site orientation of the CYP2C9 database molecules. The quality of the results obtained was excellent, with 39 of the first 44 molecules (89%) sorted by ROCS combination score having alignments that accounted for the experimentally observed site of oxidation. Transposition of the first 39 correctly aligned molecules into the CYP2C9 active site yielded an average site of metabolism to iron heme distance of 5.21 A, in good agreement with previous experimental observations. Molecular docking studies were also undertaken, but the results were less successful than the ROCS-based alignment method, indicating that ligand-based approaches with chemical typing are important in the prediction of metabolism by CYP2C9.     

CYPalleles: a web page for nomenclature of human cytochrome P450 alleles

Genetic variations in the genes encoding the cytochrome P450s (CYPs) are important determinants for interindividual differences in sensitivity to drugs and environmental chemicals as well as for the pathogenesis of several human diseases. In order to standardise the nomenclature of the rapidly increasing number of alleles described, a web page was established a few years ago. Here, we describe the present status of the web page and summarise the principles used for CYP allele nomenclature.     

Development of robust QSAR model using rapid overlay of crystal structures (ROCS) based alignment: a test case of Tubulin inhibitors

Conformational alignment is the most important step in 3D-QSAR methodology. There are various methods available to create an alignment hypothesis for the compounds being studied in 3D-QSAR. Most famous alignment methods include: alignment on a suitable template conformation, field fit alignment, database alignment, pharmacophore-based alignment, atom fit, and docking based alignment. All of the above-mentioned methods were explored previously to sample the conformational space in 3D-QSAR. Current study is dealing with the situation where most of the alignment methods were failed to produce a statistically robust 3D-QSAR model. Therefore, a relatively new alignment scheme was employed using ROCS (Rapid Overlay of Chemical Structures) method from OpenEyes. In the present study, Combretastatin A-4 based Tubulin inhibitors were used as case study. Co-crystal ligand conformation (i.e., Colchicine) in the Tubulin complex structure (PDB ID: 1SA0) was utilized as a template molecule. To date, very few applications of ROCS-based alignments in 3D-QSAR are reported in literature. Therefore, current study will serve as an addition to the existing status of using ROCS in 3D-QSAR. Genetic algorithm was utilized to build final 3D-QSAR model. Correlation obtained from final model suggesting that robust 3D-QSAR model was constructed.     

达托霉素治疗皮肤及软组织感染的快速卫生经济技术评估研究

目的通过利用快速卫生经济技术评估的工具对达托霉素治疗皮肤及软组织感染进行有效性、安全性、经济性评估,为医院药物遴选提供参考。方法通过计算机检索Pub Med、the Cochrane Library、CNKI、CBM、万方等数据库。2名评价者独立通过数据提取表的方法提取数据结果。根据纳入研究的类型,采用描述性分析对研究结论进行分类汇总。结果共纳入8篇文献,4篇为系统评价,4篇为药物经济学研究。达托霉素的有效性和安全性研究显示,其与万古霉素无显著差异;经济学研究显示,达托霉素可以作为万古霉素的替代药物。结论通过对达托霉素治疗皮肤及软组织感染的评估发现,快速卫生经济技术评估工具可作为一种简洁、快捷、易行的方法,为医院的药物遴选提供参考。     

一种快速分离纯化金葡萄球菌肠毒素C2的方法

目的 建立一种简单快捷的方法,用来从金黄色葡萄球菌的发酵液(以下简称金葡液)中纯化分离肠毒素C2(staphylococcal enterotoxin C2,SEC2).方法 金葡液首先经超滤浓缩,之后再分别经阳离子交换层析和阴离子交换层析进行选择性分离SEC2,用SDS-PAGE电泳、HPLC法检测纯度及相对分子质量,飞行质谱测定精确分子质量,对其进行N -端氨基酸序列分析.结果 分离得到的SEC2电泳纯及色谱分析纯度均达到质量分数98%以上,经各项理化指标检测均与文献一致,在等电点上表现出微不均匀性,等电点pI 为7.49和6.74,该蛋白的分子质量为27.58 ku,N -端氨基酸序列分析与文献报道的SEC2序列一致(ESQPDPTPDELHKSS),最大吸收波长为277.5 nm.结论 用该方法得到的SEC2纯度高,回收率质量分数高达50%,适宜于大批量制备SEC2.     

Topomer CoMFA: a design methodology for rapid lead optimization

To provide an objective QSAR methodology that might accelerate lead optimization, the CoMFA and topomer technologies have been merged, with surprisingly good results. A series of input structures are each broken into two or more fragments at central acyclic single bonds, while removing any core fragment structurally common to the entire series. Standard topomer 3D models are automatically constructed for each fragment, and a set of steric and electrostatic fields ("CoMFA column") is generated for each set of topomers. Application of "topomer CoMFA" to 15 3D-QSAR analyses taken from the literature (847 structures) were all successful, with an average q(2) of 0.520 (literature average q(2) = 0.636) and an average standard deviation of true prediction (SDEP) of 0.688 (literature average SDEP = 0.553) for 133 structures. Topomer CoMFA results are particularly promising as queries into virtual libraries already composed of topomer structures, to directly seek structures having increased potency. Accordingly, in 13 of the 15 such "topomer CoMFA searches" attempted, combinations of commercially offered fragments were retrieved that were predicted to be more potent than any structure described in the original publication (average predicted potency increase = 20 x), showing in principle how optimization could occur.     

A novel cyclic peptide library immobilized on gel-type beads focusing on rapid construction and characterization for comprehensive drug discovery

Medium sized molecules such as peptides and macrocycles have recently drawn much attention as potent sources of medicinal lead compounds, whereas the possibility of obtaining a practical drug from them remains limited. The present paper describes a concept of discovering novel medicinal targets or binding modes as well as lead compounds by the one-peptide-on-one-bead (OPOB) technology for comprehensive screening. The difficulty and problems in conventional drug discovery methods that generally deal with one predetermined target are considered. The building blocks used for the present libraries were selected based on previous results in development of peptidic drugs. Each constituent has the common structure of cyclic form prepared by disulfide of cysteinyl residues or thioether linkages, additionally a methionine residue was inserted for the site-specific rapid cleavage by cyanogen bromide to liberate the immobilized peptides allowing reliable characterization by MALDI-TOF-MS/MS without LC-purification. Thus, a high throughput construction method for cyclic peptide libraries as well as characterization of single bead are proposed for drug discovery.     

罗匹尼罗治疗帕金森病的快速卫生技术评估

目的： 对罗匹尼罗进行快速卫生技术评估,评估其有效性、安全性和经济性,为临床决策提供参考。方法： 系统检索相关中英文数据库,由2名专业人员根据纳入和排除标准独立筛选文献,提取数据,并进行综合分析。结果： 共纳入卫生技术评估报告1篇,系统评价/Meta分析8篇,药物经济学研究2篇。以统一帕金森病评价量表（Unified Parkinson's Disease Rating Scale,UPDRS）进行疗效评价,罗匹尼罗显著优于安慰剂,除弱于阿扑吗啡外,与其他抗帕金森病药物相比无差异。以全因退出率进行安全性评价,罗匹尼罗与其他药物相比安全性相当或更佳。国外药物经济学研究显示罗匹尼罗具有较好的经济性,但国内缺乏相关药物经济学研究。结论： 罗匹尼罗具有良好的有效性和安全性,有必要开展其药物经济学研究。     

Analysis of affinities of penicillins for a class C beta-lactamase by molecular dynamics simulations.

We present a calculation for the binding free energy difference between two complexes of the class C beta-lactamase from Enterobacter cloacae with foramidocillin (FOPC) and with piperacillin (PIPC). The calculation was carried out by means of the thermodynamic integration (TI) method implemented with molecular dynamics (MD). By use of the available crystal structure of the class C beta-lactamase from E. cloacae, the structures of the beta-lactamase-FOPC (FOPC complex) and beta-lactamase-PIPC (PIPC complex) complexes were built by molecular modeling and equilibrated with MD simulations. FOPC were gradually converted into PIPC in both the solution and the enzyme system by means of MD/TI methods during the MD simulation. The structure of the PIPC complex as derived by the MD/TI simulation was similar to that of the PIPC complex obtained from molecular modeling. The calculated difference in the free energy of binding (deltadeltaGbind) was -2.2 kcal/mol. This compares well with the experimental value of -1.5 kcal/mol. The results indicate that the binding affinity of FOPC is lower than that of PIPC because of the greater difficulty of desolvation for FOPC upon binding to the enzyme. This calculation suggests that the desolvation of the ligand, as well as its interaction with the beta-lactamase, is important in understanding the relative affinity of the ligands with beta-lactamase.     

A web application for moderation training: Initial results of a randomized clinical trial

Eighty-four heavy drinkers who responded to a newspaper recruitment advertisement were randomly assigned to receive either (a) training in a Moderate Drinking protocol via an Internet-based program (www.moderatedrinking.com) and use of the online resources of Moderation Management (MM; www.moderation.org) or (b) use of the online resources of MM alone. Follow-ups are being conducted at 3, 6, and 12 months. Results of the recently completed 3-month follow-up (86% follow-up) indicated both groups significantly reduced their drinking based on these variables: standard drinks per week, percent days abstinent, and mean estimated blood alcohol concentration (BAC) per drinking day. Both groups also significantly reduced their alcohol-related problems. Relative to the control group, the experimental group had better outcomes on percent days abstinent and log drinks per drinking day. These short-term outcome data provide evidence for the effectiveness of both the Moderate Drinking Web application and of the resources available online at MM in helping heavy drinkers reduce their drinking and alcohol-related problems.