Robust optimization of scoring functions for a target class

Target-specific optimization of scoring functions for protein–ligand docking is an effective method for significantly improving the discrimination of active and inactive molecules in virtual screening applications. Its applicability, however, is limited due to the narrow focus on, e.g., single protein structures. Using an ensemble of protein kinase structures, the publically available directory of useful decoys ligand dataset, and a novel multi-factorial optimization procedure, it is shown here that scoring functions can be tuned to multiple targets of a target class simultaneously. This leads to an improved robustness of the resulting scoring function parameters. Extensive validation experiments clearly demonstrate that (1) virtual screening performance for kinases improves significantly; (2) variations in database content affect this kind of machine-learning strategy to a lesser extent than binary QSAR models, and (3) the reweighting of interaction types is of particular importance for improved screening performance. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Identification of novel target sites and an inhibitor of the dengue virus E protein

Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus life cycle. In this study, we analyzed the pre-fusion and post-fusion structures of the dengue virus E protein to identify potential novel sites that could bind small molecules, which could interfere with the conformational transitions that mediate the fusion process. We used an in silico virtual screening approach combining three different docking algorithms (DOCK, GOLD and FlexX) to identify compounds that are likely to bind to these sites. Seven structurally diverse molecules were selected to test experimentally for inhibition of dengue virus propagation. The best compound showed an IC₅₀ in the micromolar range against dengue virus type 2. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A virtual control concept for state constrained optimal control problems

A linear elliptic control problem with pointwise state constraints is considered. These constraints are given in the domain. In contrast to this, the control acts only at the boundary. We propose a general concept using virtual control in this paper. The virtual control is introduced in objective, state equation, and constraints. Moreover, additional control constraints for the virtual control are investigated. An error estimate for the regularization error is derived as main result of the paper. The theory is illustrated by numerical tests.     

改进的粒子群算法在虚拟企业合作伙伴选择中的应用

根据虚拟企业合作伙伴选择的原则,给出了合作伙伴选择的多目标决策模型,用定量的方法对合作伙伴进行描述.同时,给出了改进的二进制粒子群优化算法,并对本文的多目标优化问题进行求解.通过仿真试验测试,证明该方法是可行性.     

Ultrafast de novo docking combining pharmacophores and combinatorics

We report on a successful de novo design approach which relies on the combination of multi-million compound combinatorial docking under receptor-based pharmacophore constraints. Inspired by a rationale by A.R. Leach et al., we document on the unification of two steps into one for ligand assembly. In the original work, fragments known to bind in protein active sites were connected forming novel ligand compounds by means of generic skeleton linkers and following a combinatorial approach. In our approach, the knowledge of fragments binding to the protein has been expressed in terms of a receptor-based pharmacophore definition. The combinatorial linking step is performed in situ during docking, starting from combinatorial libraries. Three sample scenarios growing in size and complexity (combinatorial libraries of 1 million, 1.3 million, and 22.4 million compounds) have been created to illustrate the method. Docking could be accomplished between minutes and several hours depending on the outset; the results were throughout promising. Technically, a module compatibility between FlexX(C) and FlexX-Pharm has been established. The background is explained, and the crucial points from an information scientist's perspective are highlighted.     

Fractional visco-elastic Euler–Bernoulli beam

Aim of this paper is the response evaluation of fractional visco-elastic Euler–Bernoulli beam under quasi-static and dynamic loads. Starting from the local fractional visco-elastic relationship between axial stress and axial strain, it is shown that bending moment, curvature, shear, and the gradient of curvature involve fractional operators. Solution of particular example problems are studied in detail providing a correct position of mechanical boundary conditions. Moreover, it is shown that, for homogeneous beam both correspondence principles also hold in the case of Euler–Bernoulli beam with fractional constitutive law. Virtual work principle is also derived and applied to some case studies.     

具有全新机理的DNA旋转酶抑制剂的筛选及抑菌活性

利用具有新机制的抗耐药菌DNA旋转酶抑制剂GSK299423与DNA旋转酶的晶体复合物(PDB code:2XCS)构建基于配体-受体复合物的药效团模型, 诱骗集(Decoy set)验证结果表明该药效团模型具有较强的活性识别能力. 将药效团模型与分子对接相结合用于筛选化合物库, 通过抑菌活性测定, 获得了具有抗多药耐药菌活性的DNA旋转酶抑制剂LTH02.     

求解水中加肋板声辐射特性的虚拟声源法*

发展一种利用虚拟声源离散声场的方法求解加肋板在水中的声振耦合问题。由波叠加原理和单元体积速度匹配的原则,根据离散的结构单元满足的动力方程和结构与介质的交界相容性条件,确定虚拟声源强度,计算结构的声辐射功率。本文以简支矩形加肋板为例,在不获得结构表面振速和声压的情况下,计算了结构在水中的声辐射功率,并与解析方法计算的结果进行了比较,表明了该方法具有较好的计算精度。     

用于开口声辐射控制的虚拟声屏障实现 方法及机理研究*

建筑物通常留有开口以便人员物料的进出及室内的自然通风采光,但这些开口也是噪声传播的途径。传统被动噪声控制方法需要将开口封闭,且对低频噪声的控制效果不好,故引入有源噪声控制技术降低室内声源通过开口的声辐射。基于惠更斯原理,均布开口的次级源和误差传声器构成的平面型虚拟声屏障可以实现对开口声辐射的有效控制,数值仿真和实验已证明其有效性。将次级源安装在开口边界更有利于保留开口的功能且方便实际安装,但这样的单层边界虚拟声屏障降噪效果存在上限,仅能在低频段实现全局控制。和单层边界次级源相比,双层边界次级源可显著提高降噪量和有效降噪频率上限。该文回顾了开口声辐射有源控制的相关工作,并讨论了未来可能的研究方向。