抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

J. Appl. Cryst.の発刊に際して

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

Glide's ability to identify active compounds in a database screen is characterized by applying Glide to a diverse set of nine protein receptors. In many cases, two, or even three, protein sites are employed to probe the sensitivity of the results to the site geometry. To make the database screens as realistic as possible, the screens use sets of “druglike” decoy ligands that have been selected to be representative of what we believe is likely to be found in the compound collection of a pharmaceutical or biotechnology company. Results are presented for releases 1.8, 2.0, and 2.5 of Glide. The comparisons show that average measures for both “early” and “global” enrichment for Glide 2.5 are 3 times higher than for Glide 1.8 and more than 2 times higher than for Glide 2.0 because of better results for the least well-handled screens. This improvement in enrichment stems largely from the better balance of the more widely parametrized GlideScore 2.5 function and the inclusion of terms that penalize ligand−protei...

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Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.

Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.

Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments

The MM-PBSA approach has become a popular method for calculating binding affinities of biomolecular complexes. Published application examples focus on small test sets and few proteins and, hence, are of limited relevance in assessing the general validity of this method. To further characterize MM-PBSA, we report on a more extensive study involving a large number of ligands and eight different proteins. Our results show that applying the MM-PBSA energy function to a single, relaxed complex structure is an adequate and sometimes more accurate approach than the standard free energy averaging over molecular dynamics snapshots. The use of MM-PBSA on a single structure is shown to be valuable (a) as a postdocking filter in further enriching virtual screening results, (b) as a helpful tool to prioritize de novo design solutions, and (c) for distinguishing between good and weak binders (DeltapIC(50) > or = 2-3), but rarely to reproduce smaller free energy differences.

Validation and use of the MM-PBSA approach for drug discovery.

In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.

Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase

Two new docking programs FRED (OpenEye Scientific Software) and Glide (Schrodinger, Inc.) in combination with various scoring functions implemented in these programs have been evaluated against a variety of seven protein targets (cyclooxygenase-2, estrogen receptor, p38 MAP kinase, gyrase B, thrombin, gelatinase A, neuraminidase) in order to assess their accuracy in virtual screening. Sets of known inhibitors were added to and ranked relative to a random library of drug-like compounds. Performance was compared in terms of enrichment factors and CPU time consumption. Results and specific features of the two new tools are discussed and compared to previously published results using FlexX (Tripos, Inc.) as a docking engine. In addition, general criteria for the selection of docking algorithms and scoring functions based on binding-site characteristics of specific protein targets are proposed. Figure Enrichment factors obtained with FlexX, Glide and FRED docking engines in combination with different scoring functions for seven selected targets with highly variable binding sites

Binding site characteristics in structure-based virtual screening: evaluation of current docking tools

Replacing central elements of known active structures is a common procedure to enter new compound classes. Different computational methods have already been developed to help with this task, varying in the description of possible replacements, the query input, and the similarity measure used. In this paper, a novel approach for scaffold replacement and a corresponding software tool, called Recore, is introduced. In contrast to prior methods, our main objective was to combine the following three properties in one tool:  to avoid structures with strained conformations, to enable the exploration of large search spaces, and to allow interactive use through short response times. We introduce a new technique employing 3D fragments generated by combinatorial enumeration of cuts. It allows focusing on fragments suitable for scaffold replacement while retaining conformational information of the corresponding crystal structures. Based on this idea, we present an algorithm utilizing a geometric rank searching approa...

Tanja Schulz-Gasch

Papers

Validation and use of the MM-PBSA approach for drug discovery.

Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase

Binding site characteristics in structure-based virtual screening: evaluation of current docking tools

Recore: A Fast and Versatile Method for Scaffold Hopping Based on Small Molecule Crystal Structure Conformations

Scoring functions for protein-ligand interactions: a critical perspective.