VSDMIP: virtual screening data management on an integrated platform

A novel software (VSDMIP) for the virtual screening (VS) of chemical libraries integrated within a MySQL relational database is presented. Two main features make VSDMIP clearly distinguishable from other existing computational tools: (i) its database, which stores not only ligand information but also the results from every step in the VS process, and (ii) its modular and pluggable architecture, which allows customization of the VS stages (such as the programs used for conformer generation or docking), through the definition of a detailed workflow employing user-configurable XML files. VSDMIP, therefore, facilitates the storage and retrieval of VS results, easily adapts to the specific requirements of each method and tool used in the experiments, and allows the comparison of different VS methodologies. To validate the usefulness of VSDMIP as an automated tool for carrying out VS several experiments were run on six protein targets (acetylcholinesterase, cyclin-dependent kinase 2, coagulation factor Xa, estrogen receptor alpha, p38 MAP kinase, and neuraminidase) using nine binary (actives/inactive) test sets. The performance of several VS configurations was evaluated by means of enrichment factors and receiver operating characteristic plots. ángel R. Ortiz deceased on May 5, 2008.     

IVSPlat 1.0: an integrated virtual screening platform with a molecular graphical interface

Background  

The virtual screening (VS) of lead compounds using molecular docking and pharmacophore detection is now an important tool in drug discovery. VS tasks typically require a combination of several software tools and a molecular graphics system. Thus, the integration of all the requisite tools in a single operating environment could reduce the complexity of running VS experiments. However, only a few freely available integrated software platforms have been developed.     

An integrated approach to knowledge-driven structure-based virtual screening

In many practical applications of structure-based virtual screening (VS) ligands are already known. This circumstance requires that the obtained hits need to satisfy initial made expectations i.e., they have to fulfill a predefined binding pattern and/or lie within a predefined physico-chemical property range. Based on the RApid Index-based Screening Engine (RAISE) approach, we introduce cRAISE—a user-controllable structure-based VS method. It efficiently realizes pharmacophore-guided protein-ligand docking to assess the library content but thereby concentrates only on molecules that have a chance to fulfill the given binding pattern. In order to focus only on hits satisfying given molecular properties, library profiles can be utilized to simultaneously filter compounds. cRAISE was evaluated on a range of strict to rather relaxed hypotheses with respect to its capability to guide binding-mode predictions and VS runs. The results reveal insights into a guided VS process. If a pharmacophore model is chosen appropriately, a binding mode below 2 Å is successfully reproduced for 85 % of well-prepared structures, enrichment is increased up to median AUC of 73 %, and the selectivity of the screening process is significantly enhanced leading up to seven times accelerated runtimes. In general, cRAISE supports a versatile structure-based VS approach allowing to assess hypotheses about putative ligands on a large scale.     

MedusaScore: an accurate force field-based scoring function for virtual drug screening

Virtual screening is becoming an important tool for drug discovery. However, the application of virtual screening has been limited by the lack of accurate scoring functions. Here, we present a novel scoring function, MedusaScore, for evaluating protein-ligand binding. MedusaScore is based on models of physical interactions that include van der Waals, solvation, and hydrogen bonding energies. To ensure the best transferability of the scoring function, we do not use any protein-ligand experimental data for parameter training. We then test the MedusaScore for docking decoy recognition and binding affinity prediction and find superior performance compared to other widely used scoring functions. Statistical analysis indicates that one source of inaccuracy of MedusaScore may arise from the unaccounted entropic loss upon ligand binding, which suggests avenues of approach for further MedusaScore improvement.     

Shapelets: possibilities and limitations of shape-based virtual screening

Complementarity of molecular surfaces is crucial for molecular recognition. A method for representation of molecular shape is presented. We decompose the molecular surface into commensurate patches with defined shape by fitting hyperbolical paraboloids onto a triangulated isosurface of the Gaussian model of a molecule. As a result of this decomposition we obtain a 3D graph representation of the molecular shape, which can be used for complete and partial shape matching and isosteric group searching. To point out the possibilities and limitations of shape-only models, we challenged our method by three scenarios in a virtual screening contest: rigid body alignment, consensus shape filtering, and target-specific screening.     

Cell-based high content screening using an integrated microfluidic device

High content screening (HCS) has quickly established itself as a core technique in the early stage of drug discovery for secondary compound screening. It allows several independent cellular parameters to be measured in a single cell or populations of cells in a single assay. In this work, we describe high content screening for the multiparametric measurement of cellular responses in human liver carcinoma (HepG2) cells using an integrated microfluidic device. This device consists of multiple drug gradient generators and parallel cell culture chambers, in which the processes of liquid dilution and diffusion, micro-scale cell culture, cell stimulation and cell labeling can be integrated into a single device. The simple assay provides multiparametric measurements of plasma membrane permeability, nuclear size, mitochondrial transmembrane potential and intracellular redox states in anti-cancer drug-induced apoptosis of HepG2 cells. The established platform is able to rapidly extract the maximum of information from tumor cells in response to several drugs varying in concentration, with minimal sample and less time, which is very useful for basic biomedical research and cancer treatment.     

Enabling drug discovery project decisions with integrated computational chemistry and informatics

Computational chemistry/informatics scientists and software engineers in Genentech Small Molecule Drug Discovery collaborate with experimental scientists in a therapeutic project-centric environment. Our mission is to enable and improve pre-clinical drug discovery design and decisions. Our goal is to deliver timely data, analysis, and modeling to our therapeutic project teams using best-in-class software tools. We describe our strategy, the organization of our group, and our approaches to reach this goal. We conclude with a summary of the interdisciplinary skills required for computational scientists and recommendations for their training.     

An integrated instrument control and informatics system for combinatorial materials research

The use of high-throughput synthesis and characterization techniques is increasingly prevalent in materials science research. We describe the London University Search Instrument, a research apparatus designed for the high-throughput synthesis and characterization of thick-film sample libraries of ceramic compounds. The instrument is constructed largely from commodity components, which pose particular engineering challenges for achieving the automated operation required for efficient high-throughput experimentation. This paper describes the architecture and implementation of the software system that provides integrated instrument control and data management functions.     

Development of a photolabile carbonyl-protecting group toolbox

New salicyl alcohol derived photolabile carbonyl protecting groups have been developed, and the effect of substituents on the photochemical properties of photolabile protecting groups (PPGs) has been studied. The 3-(dimethylamino)phenyl groups at the α position prove to be important to the efficiency of the deprotection reactions, as shown in the photo reactions of the acetal 9. On the other hand, expansion of the salicyl alcohol's benzene skeleton to naphthalene does not improve the photochemical properties of PPGs. A neutral protecting protocol has been generalized to new PPGs with α,α-diaryl salicyl alcohol backbone. Thus, installation of PPGs onto aldehydes is readily achieved at 140 °C without using any other chemical reagents. These PPGs are stable under acidic conditions typical for hydrolyzing acetals and constitute orthogonal protecting groups with traditional 1,3-dioxane/1,3-dioxolane for carbonyl compounds. Highly efficient release of carbohydrate molecules is demonstrated, which can be potentially useful in site-specific release and immobilization of carbohydrates for preparation of high-density microarrays. With the enriched PPG toolbox, PPGs are divided into three subgroups based on their UV absorption profiles. PPGs from different subgroups can be sequentially removed by using different UV irradiation wavelengths. For PPGs absorbing UVA (λ >315 nm), photochemical deprotection can be carried out with sunlight in high yields.     

FRED pose prediction and virtual screening accuracy

Results of a previous docking study are reanalyzed and extended to include results from the docking program FRED and a detailed statistical analysis of both structure reproduction and virtual screening results. FRED is run both in a traditional docking mode and in a hybrid mode that makes use of the structure of a bound ligand in addition to the protein structure to screen molecules. This analysis shows that most docking programs are effective overall but highly inconsistent, tending to do well on one system and poorly on the next. Comparing methods, the difference in mean performance on DUD is found to be statistically significant (95% confidence) 61% of the time when using a global enrichment metric (AUC). Early enrichment metrics are found to have relatively poor statistical power, with 0.5% early enrichment only able to distinguish methods to 95% confidence 14% of the time.     

VSDMIP 1.5: an automated structure- and ligand-based virtual screening platform with a PyMOL graphical user interface

A graphical user interface (GUI) for our previously published virtual screening (VS) and data management platform VSDMIP (Gil-Redondo et al. J Comput Aided Mol Design, 23:171–184, 2009) that has been developed as a plugin for the popular molecular visualization program PyMOL is presented. In addition, a ligand-based VS module (LBVS) has been implemented that complements the already existing structure-based VS (SBVS) module and can be used in those cases where the receptor’s 3D structure is not known or for pre-filtering purposes. This updated version of VSDMIP is placed in the context of similar available software and its LBVS and SBVS capabilities are tested here on a reduced set of the Directory of Useful Decoys database. Comparison of results from both approaches confirms the trend found in previous studies that LBVS outperforms SBVS. We also show that by combining LBVS and SBVS, and using a cluster of ~100 modern processors, it is possible to perform complete VS studies of several million molecules in less than a month. As the main processes in VSDMIP are 100% scalable, more powerful processors and larger clusters would notably decrease this time span. The plugin is distributed under an academic license upon request from the authors.     

DOVIS 2.0: an efficient and easy to use parallel virtual screening tool based on AutoDock 4.0

Background  

Small-molecule docking is an important tool in studying receptor-ligand interactions and in identifying potential drug candidates. Previously, we developed a software tool (DOVIS) to perform large-scale virtual screening of small molecules in parallel on Linux clusters, using AutoDock 3.05 as the docking engine. DOVIS enables the seamless screening of millions of compounds on high-performance computing platforms. In this paper, we report significant advances in the software implementation of DOVIS 2.0, including enhanced screening capability, improved file system efficiency, and extended usability.     

StructRank: a new approach for ligand-based virtual screening

Screening large libraries of chemical compounds against a biological target, typically a receptor or an enzyme, is a crucial step in the process of drug discovery. Virtual screening (VS) can be seen as a ranking problem which prefers as many actives as possible at the top of the ranking. As a standard, current Quantitative Structure-Activity Relationship (QSAR) models apply regression methods to predict the level of activity for each molecule and then sort them to establish the ranking. In this paper, we propose a top-k ranking algorithm (StructRank) based on Support Vector Machines to solve the early recognition problem directly. Empirically, we show that our ranking approach outperforms not only regression methods but another ranking approach recently proposed for QSAR ranking, RankSVM, in terms of actives found.     

Development and characterization of an integrated silicon micro flow cytometer

This paper describes an innovative integrated micro flow cytometer that presents a new arrangement for the excitation/detection system. The sample liquid, containing the fluorescent marked particles/cells under analysis, is hydrodynamically squeezed into a narrow stream by two sheath flows so that the particles/cells flow individually through a detection region. The detection of the particles/cells emitted fluorescence is carried out by using a collection fiber placed orthogonally to the flow. The device is based on silicon hollow core antiresonant reflecting optical waveguides (ARROWs). ARROW geometry allows one to use the same channel to guide both the sample stream and the fluorescence excitation light, leading to a simplification of the optical configuration and to an increase of the signal-to-noise ratio. The integrated micro flow cytometer has been characterized by using biological samples marked with standard fluorochromes. The experimental investigation confirms the success of the proposed microdevice in the detection of cells. An erratum to this article can be found at     

Impact of scoring functions on enrichment in docking-based virtual screening: an application study on renin inhibitors

The docking program LigandFit/Cerius(2) has been used to perform shape-based virtual screening of databases against the aspartic protease renin, a target of determined three-dimensional structure. The protein structure was used in the induced fit binding conformation that occurs when renin is bound to the highly active renin inhibitor 1 (IC(50) = 2 nM). The scoring was calculated using several different scoring functions in order to get insight into the predictability of the magnitude of binding interactions. A database of 1000 diverse and druglike compounds, comprised of 990 members of a virtual database generated by using the iLib diverse software and 10 known active renin inhibitors, was docked flexibly and scored to determine appropriate scoring functions. All seven scoring functions used (LigScore1, LigScore2, PLP1, PLP2, JAIN, PMF, LUDI) were able to retrieve at least 50% of the active compounds within the first 20% (200 molecules) of the entire test database. A hit rate of 90% in the top 1.4% resulted using the quadruple consensus scoring of LigScore2, PLP1, PLP2, and JAIN. Additionally, a focused database was created with the iLib diverse software and used for the same procedure as the test database. Docking and scoring of the 990 focused compounds and the 10 known actives were performed. A hit rate of 100% in the top 8.4% resulted with use of the triple consensus scoring of PLP1, PLP2, and PMF. As expected, a ranking of the known active compounds within the focused database compared to the test database was observed. Adequate virtual screening conditions were derived empirically. They can be used for proximate docking and scoring application of compounds with putative renin inhibiting potency.