Tackling the conformational sampling of larger flexible compounds and macrocycles in pharmacology and drug discovery

Computational conformational sampling underpins much of molecular modeling and design in pharmaceutical work. The sampling of smaller drug-like compounds has been an active area of research. However, few studies have tested in details the sampling of larger more flexible compounds, which are also relevant to drug discovery, including therapeutic peptides, macrocycles, and inhibitors of protein–protein interactions. Here, we investigate extensively mainstream conformational sampling methods on three carefully curated compound sets, namely the ‘Drug-like’, larger ‘Flexible’, and ‘Macrocycle’ compounds. These test molecules are chemically diverse with reliable X-ray protein-bound bioactive structures. The compared sampling methods include Stochastic Search and the recent LowModeMD from MOE, all the low-mode based approaches from MacroModel, and MD/LLMOD recently developed for macrocycles. In addition to default settings, key parameters of the sampling protocols were explored. The performance of the computational protocols was assessed via (i) the reproduction of the X-ray bioactive structures, (ii) the size, coverage and diversity of the output conformational ensembles, (iii) the compactness/extendedness of the conformers, and (iv) the ability to locate the global energy minimum. The influence of the stochastic nature of the searches on the results was also examined. Much better results were obtained by adopting search parameters enhanced over the default settings, while maintaining computational tractability. In MOE, the recent LowModeMD emerged as the method of choice. Mixed torsional/low-mode from MacroModel performed as well as LowModeMD, and MD/LLMOD performed well for macrocycles. The low-mode based approaches yielded very encouraging results with the flexible and macrocycle sets. Thus, one can productively tackle the computational conformational search of larger flexible compounds for drug discovery, including macrocycles.     

三种输尿管镜治疗输尿管上段结石的疗效比较

目的:比较半硬性输尿管镜、输尿管软镜、孙氏末段可弯输尿管镜治疗输尿管上段结石的临床疗效,为临床上治疗方式的选择提供参考。方法:回顾性分析2015年8月到2017年12月间于上海市第十人民医院泌尿外科因输尿管上段结石行输尿管镜下钬激光治疗的515例患者的临床资料。按照所用输尿管镜类型分为3组:硬镜组(给予半硬性输尿管镜治疗)297例,软镜组172例(给予输尿管软镜治疗),孙氏镜组(给予孙氏末段可弯输尿管镜治疗)46例。比较三组的手术时间、一期清石率、术后住院时间及术中、术后并发症。结果:硬镜组、软镜组、孙氏镜组清石率分别为81.5%、94.2%、95.7%,其中软镜组、孙氏镜组清石率显著高于硬镜组(P0.05)。硬镜组、软镜组、孙氏镜组术中并发症发生率分别为18.9%、5.8%、4.3%,其中硬镜组术中并发症发生率显著高于软镜组和孙氏镜组(P0.05),三组术后并发症发生率整体比较差异无统计学意义(P0.05)。硬镜组、软镜组、孙氏镜组平均手术时间分别为(28.6±6.2)min、(49.4±12.4)min、(26.1±6.5)min,软镜组平均手术时间显著高于硬镜组及孙氏镜组,差异有统计学意义(均P0.05)。硬镜组、软镜组、孙氏镜组平均住院时间分别为(5.4±3.2)d、(6.7±5.7)d、(5.0±2.5)d,软镜组住院时间显著高于硬镜组和孙氏镜组,差异有统计学意义(均P0.05)。结论:软镜清石效果和手术安全性较硬镜更有优势,但手术耗时长,患者术后住院时间长。孙氏镜有望成为治疗输尿管上段结石的更佳选择。     

Two new pH-controlled metal-organic frameworks based on polynuclear secondary building units with conformation-flexible cyclohexane-1,2,4,5-tetracarboxylate ligand

By regulating the pH values, two new zinc(II) coordination polymers, formulated as [Zn₄(μ₇-CTA^I)(μ₃-OH)(μ₂-OH)₃(H₂O)₂]_n·2n(H₂O) (1), [Zn₂(μ₇-CTA^II)(H₂O)₃]_n (2) have been prepared by a flexible ligand, cyclohexane-1,2,4,5-tetracarboxylic acid (H₄CTA) under hydrothermal conditions. Complex 1 exhibits a two-dimensional binodal (3,6)-connected topological network containing rare octanuclear zinc(II) clusters as the secondary building units (SBU1). Complex 2 displays a three-dimensional binodal (4,8)-connected topological network containing unusual Zn₄(COO)₆ secondary building units (SBU2). And importantly, the conformation of H₄CTA in 1 exhibits (a,e,e,a) fashion and transforms to thermodynamically more stable conformation (e,a,e,e) type in 2 by pH-controlled. In addition, both of the complexes show strong photoluminescence at room temperature, and may be good candidates for potential luminescence materials.     

Flexible chitin films: structural studies

Chitin gels were transformed into thin, flexible chitin films with minimal dimensional shrinkage and maximum flexibility and thickness in the range of 25-80 microm by a cold-press process. Solvent residue was removed by heating the films at 50 degrees C for 12 h, followed by rinsing in 95% ethanol. The crystallinity and mechanical properties of the flexible chitin films were found to be a function of the amount of shrinkage from the gel to the final film that was obtained. For 28-microm thick films with 30% shrinkage, transparency of up to 90% was found. X-ray diffractometry (XRD) showed that the number of diffraction peaks appearing at 2theta;=23 degrees and 2theta;=27 degrees became increasingly sharper with shrinkage. Topographical information obtained from scanning electron microscopy (SEM) and atomic force microscopy (AFM) attributed the structural morphology of the films to the formation of sub-microscopic micelles. Scanning transmission electron microscopy (STEM) showed that shrinkage resulted in coarser microstructure, affecting tensile properties, where the ductility and toughness were proportional to the amount of shrinkage. These flexible chitin films have potential as wound dressing materials.     

A new approach for evaluating flexible working hours

Recent studies on flexible working hours show at least some of these working time arrangements seem to be associated with impairing effects of health and well-being. According to available evidence, variability of working hours seems to play an important role. The question, however, is how this variability can be assessed and used to explain or predict impairments. Based on earlier methods used to assess shift-work effects, a time series analysis approach was applied to the matter of flexible working hours. Data on the working hours of 4 week's length of 137 respondents derived from a survey on flexible work hours involving 15 companies of different production and service sectors in Germany were converted to time series and analyzed by spectral analysis. A cluster analysis of the resulting power spectra yielded 5 clusters of flexible work hours. Analyzing these clusters for differences in reported impairments showed that workers who showed suppression of circadian and weekly rhythms experienced severest impairments, especially in circadian controlled functions like sleep and digestion. The results thus indicate that analyzing the periodicity of flexible working hours seems to be a promising approach for predicting impairments which should be investigated further in the future.     

Multi-component model of intramural hematoma

A novel multi-component model is introduced for studying interaction between blood flow and deforming aortic wall with intramural hematoma (IMH). The aortic wall is simulated by a composite structure submodel representing material properties of the three main wall layers. The IMH is described by a poroelasticity submodel which takes into account both the pressure inside hematoma and its deformation. The submodel of the hematoma is fully coupled with the aortic submodel as well as with the submodel of the pulsatile blood flow. Model simulations are used to investigate the relation between the peak wall stress, hematoma thickness and permeability in patients of different age. The results indicate that an increase in hematoma thickness leads to larger wall stress, which is in agreement with clinical data. Further simulations demonstrate that a hematoma with smaller permeability results in larger wall stress, suggesting that blood coagulation in hematoma might increase its mechanical stability. This is in agreement with previous experimental observations of coagulation having a beneficial effect on the condition of a patient with the IMH.     

Advances in organic electro-optic materials and processing

Frequency-agile, femtosecond Hyper-Rayleigh scattering measurements are used to test the utility of density functional theory calculations for suggesting chromophore structures with improved molecular first hyperpolarizability, β. A tricyanopyrroline acceptor is shown to yield a factor of approximately three improvement over the commonly used tricyanofuran acceptor. The combination of improved chromophores and incorporation of chromophores into novel nanostructured lattices is leading to routine realization of electro-optic coefficients greater than 100 pm/V at telecommunication wavelengths. In this communication, the use of nanoimprint lithography to stamp out active and passive optical circuitry is also demonstrated. The potential for low-cost, mass production of electro-optic devices, including conformal and flexible devices, is suggested.     

Robustness of individual and marginal model-based estimates: A sensitivity analysis of flexible parametric models

BackgroundFlexible parametric survival models (FPMs) are commonly used in epidemiology. These are preferred as a wide range of hazard shapes can be captured using splines to model the log-cumulative hazard function and can include time-dependent effects for more flexibility. An important issue is the number of knots used for splines. The reliability of estimates are assessed using English data for 10 cancer types and the use of online interactive graphs to enable a more comprehensive sensitivity analysis at the control of the user is demonstrated.MethodsSixty FPMs were fitted to each cancer type with varying degrees of freedom to model the baseline excess hazard and the main and time-dependent effect of age. For each model, we obtained age-specific, age-group and internally age-standardised relative survival estimates. The Akaike Information Criterion and Bayesian Information Criterion were also calculated and comparative estimates were obtained using the Ederer II and Pohar Perme methods. Web-based interactive graphs were developed to present results.ResultsAge-standardised estimates were very insensitive to the exact number of knots for the splines. Age-group survival is also stable with negligible differences between models. Age-specific estimates are less stable especially for the youngest and oldest patients, of whom there are very few, but for most scenarios perform well.ConclusionAlthough estimates do not depend heavily on the number of knots, too few knots should be avoided, as they can result in a poor fit. Interactive graphs engage researchers in assessing model sensitivity to a wide range of scenarios and their use is highly encouraged.     

A mechanically strong, flexible and conductive film based on bacterial cellulose/graphene nanocomposite

A highly flexible nanocomposite film of bacterial cellulose (BC) and graphene oxide (GO) with a layered structure was presented using the vacuum-assisted self-assembly technique. Microscopic and X-ray diffraction measurements demonstrated that the GO nanosheets were uniformly dispersed in the BC matrix. The interactions between BC and GO were studied by Fourier transformation infrared spectroscopy. Compared with pristine BC, the integration of 5 wt% GO resulted in 10% and 20% increase in Young's modulus and tensile strength of the composite film. The electrical conductivity of the composite film containing 1 wt% GO after in situ reduction showed a remarkable increase by 6 orders of magnitude compared with the insulated BC.     

第三军医大学西南医院呼吸科

支气管镜在呼吸系统疾病的诊治中有着非常广泛的应用,也是作为呼吸专科医师所必须掌握的一项临床技能。但是在对该项技术熟练之前,不能允许在病人身体直接操作,这样对呼吸专科医师的临床培训造成了较大困难。近年来,我院采用了美国模拟电子内镜教学系统进行培训,取得了满意的效果。通过该系统的训练,培训学员能对支气管镜的操作流程、操作技巧和手法,镜下气管,各叶、段支气管走行和解剖形态,病变的定位和镜下形态,以及如何对病变进行活检、支气管灌洗和出现并发症时怎样处理等,均有较为深刻的体会,并可获得多次反复练习的机会,培训所需时间也明显缩短。