In vitro evaluation of novel inhibitors against the NS2B-NS3 protease of dengue fever virus type 4.

The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3pro) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3pro. Thirty-six compounds were selected for in vitro assay against NS2B-NS3pro expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC50 values of 3.9 ± 0.6-86.7 ± 3.6 µM. Three strong NS2B-NS3pro inhibitors were further confirmed as competitive inhibitors with Ki values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 µM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3pro active site with inhibition compounds were also identified.

Self-similarity in the classification of finite-size scaling functions for toroidal boundary conditions.

The conventional periodic boundary conditions in two dimensions are extended to general boundary conditions, prescribed by primitive vector pairs that may not coincide with the coordinate axes. This extension is shown to be unambiguously specified by the twisting scheme. Equivalent relations between different twist settings are constructed explicitly. The classification of finite-size scaling functions is discussed based on the equivalent relations. A self-similar pattern for distinct classes of finite-size scaling functions is shown to appear on the plane that parametrizes the toroidal geometry.

Master equation approach to folding kinetics of lattice polymers based on conformation networks.

Based on the master equation with the inherent structure of conformation network, the authors investigate some important issues in the folding kinetics of lattice polymers. First, the topologies of conformation networks are discussed. Moreover, a new scheme of implementing Metropolis algorithm, which fulfills the condition of detailed balance, is proposed. Then, upon incorporating this new scheme into the geometric structure of conformation network the authors provide a theorem which can be used to place an upper bound on relaxation time. To effectively identify the kinetic traps of folding, the authors also introduce a new quantity, which is employed from the continuous time Monte Carlo method, called rigidity factor. Throughout the discussions, the authors analyze the results for different move sets to demonstrate the methods and to study the features of the kinetics of folding.

Grid-enabled high-throughput in silico screening against influenza A neuraminidase.

Encouraged by the success of the first EGEE biomedical data challenge against malaria (WISDOM), the second data challenge battling avian flu was kicked off in April 2006 to identify new drugs for the potential variants of the influenza A virus. Mobilizing thousands of CPUs on the Grid, the six-week-long high-throughput screening activity has fulfilled over 100 CPU years of computing power and produced around 600 gigabytes of results on the Grid for further biological analysis and testing. In the paper, we demonstrate the impact of a worldwide Grid infrastructure to efficiently deploy large-scale virtual screening to speed up the drug design process. Lessons learned through the data challenge activity are also discussed.

Partition functions and finite-size scalings of Ising model on helical tori.

The exact closed forms of the partition functions of a two-dimensional Ising model on square lattices with twisted boundary conditions are given. The constructions of helical tori are unambiguously related to the twisted boundary conditions by virtue of the SL(2, Z) transforms. The numerical analyses on the deviations of the specific-heat peaks away from the bulk critical temperature reveal that the finite-size effect of herical tori is independent of the chirality.

A complexity reduction algorithm for analysis and annotation of large genomic sequences.

DNA is a universal language encrypted with biological instruction for life. In higher organisms, the genetic information is preserved predominantly in an organized exon/intron structure. When a gene is expressed, the exons are spliced together to form the transcript for protein synthesis. We have developed a complexity reduction algorithm for sequence analysis (CRASA) that enables direct alignment of cDNA sequences to the genome. This method features a progressive data structure in hierarchical orders to facilitate a fast and efficient search mechanism. CRASA implementation was tested with already annotated genomic sequences in two benchmark data sets and compared with 15 annotation programs (10 ab initio and 5 homology-based approaches) against the EST database. By the use of layered noise filters, the complexity of CRASA-matched data was reduced exponentially. The results from the benchmark tests showed that CRASA annotation excelled in both the sensitivity and specificity categories. When CRASA was applied to the analysis of human Chromosomes 21 and 22, an additional 83 potential genes were identified. With its large-scale processing capability, CRASA can be used as a robust tool for genome annotation with high accuracy by matching the EST sequences precisely to the genomic sequences.

Evolution and structure formation of the distribution of partition function zeros: triangular type Ising lattices with cell decoration.

The distribution of partition function zeros of the two-dimensional Ising model in the complex temperature plane is studied within the context of triangular decorated lattices and their triangle-star transformations. Exact recursion relations for the zeros are deduced for the description of the evolution of the distribution of the zeros subject to the change of decoration level. In the limit of infinite decoration level, the decorated lattices essentially possess the Sierpinski gasket or its triangle-star transformation as the inherent structure. The positions of the zeros for the infinite decorated lattices are shown to coincide with the ones for the Sierpinski gasket or its triangle-star transformation, and the distributions of zeros all appear to be a union of infinite scattered points and a Jordan curve, which is the limit of the scattered points.

Energy landscape paving for X-ray structure determination of organic molecules.

The efficiency of a recently proposed novel global optimization method, energy landscape paving (ELP), is evaluated with regard to the problem of crystal structure determination from simulated X-ray diffraction data comprising integrated diffraction intensities. The new approach has been tested using the example of 9-(methylamino)-1H-phenalen-1-one 1,4-dioxan-2-y1 hydroperoxide solvate (C14H11NO.C4H8O4). The results indicate that, for this example, ELP outperforms standard techniques such as simulated annealing.