Convergent validity and reliability of a novel repeated agility protocol in junior rugby league players.

Rugby league involves repeated, complex, and high intensity change-of-direction (COD) movements with no existing test protocols that specifically assesses these multiple physical fitness components simultaneously. Thus, the current study examined the convergent validity of a repeated Illinois Agility (RIA) protocol with the repeated T-agility protocol, and the repeatability of the RIA protocol in adolescent Rugby League players. Furthermore, aerobic capacity and anaerobic and COD performance were assessed to determine whether these physical qualities were important contributors to the RIA protocol.

Virtual Screening in the Cloud: How Big Is Big Enough?

Virtual screening is a standard tool in Computer-Assisted Drug Design (CADD). Early in a project, it is typical to use ligand-based similarity search methods to find suitable hit molecules. However, the number of compounds which can be screened and the time required are usually limited by computational resources.

The Effect of a Resistance Training Session on Physiological and Thermoregulatory Measures of Sub-maximal Running Performance in the Heat in Heat-Acclimatized Men.

Background: The current study examined the acute effects of a lower body resistance training (RT) session on physiological and thermoregulatory measures during a sub-maximal running protocol in the heat in heat-acclimatized men. Ten resistance-untrained men (age 27.4 ± 4.

Leaving us with fond memories, smiles, SMILES and, alas, tears: a tribute to David Weininger, 1952-2016.

David Weininger's career, accomplishments, genius, and friendship are warmly remembered by several of his colleagues, friends, and admirers.

Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop.

Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank (PDB) archive, ∼75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery and design, and the goodness-of-fit of ligand models to electron-density maps vary widely across the archive.

The statistics of virtual screening and lead optimization.

Analytic formulae are used to estimate the error for two virtual screening metrics, enrichment factor and area under the ROC curve. These analytic error estimates are then compared to bootstrapping error estimates, and shown to have excellent agreement with respect to area under the ROC curve and good agreement with respect to enrichment factor. The major advantage of the analytic formulae is that they are trivial to calculate and depend only on the number of actives and inactives and the measured value of the metric, information commonly reported in papers.

Factors determining penetrance in familial atypical haemolytic uraemic syndrome.

Background: Inherited abnormalities of complement are found in ∼60% of patients with atypical haemolytic uraemic syndrome (aHUS). Such abnormalities are not fully penetrant. In this study, we have estimated the penetrance of the disease in three families with a CFH mutation (c.

Efficient calculation of SAMPL4 hydration free energies using OMEGA, SZYBKI, QUACPAC, and Zap TK.

Several submissions for the SAMPL4 hydration free energy set were calculated using OpenEye tools, including many that were among the top performing submissions. All of our best submissions used AM1BCC charges and Poisson-Boltzmann solvation. Three submissions used a single conformer for calculating the hydration free energy and all performed very well with mean unsigned errors ranging from 0.

Conformer generation with OMEGA: learning from the data set and the analysis of failures.

We recently published a high quality validation set for testing conformer generators, consisting of structures from both the PDB and the CSD (Hawkins, P. C. D.

Call for Papers: GRC, CADD, and statistics, and all that.

Molecular modeling and the art of computer-aided drug discovery seldom make much use of statistics, despite being fields that can not calculate important properties with great reliability. The 2013 CADD Gordon conference intends to examine what prevents a more effective use of statistics in routine modeling and to raise consciousness as to what is possible. Practical methods will be discussed, deeper issues in applying standard approaches addressed and research on successes and failures in other disciplines presented by invited experts.

Essential considerations for using protein-ligand structures in drug discovery.

Protein-ligand structures are the core data required for structure-based drug design (SBDD). Understanding the error present in this data is essential to the successful development of SBDD tools. Methods for assessing protein-ligand structure quality and a new set of identification criteria are presented here.

The character of molecular modeling.

In asking what progress might occur in molecular modeling in the next 25 years it is worth asking what progress has been made in the last twenty-five. In doing so it is hard to be optimistic for the future of the field unless a greater commitment is made to basic science.

Application of the Gaussian dielectric boundary in Zap to the prediction of protein pKa values.

The results of two rounds of blind pK(a) predictions for ionizable residues in staphylococcal nuclease using OpenEye's legacy protein pK(a) prediction program based on the Zap Poisson-Boltzmann solver were submitted to the 2009 prediction challenge organized by the Protein pK(a) Cooperative and first round predictions were discussed at the corresponding June 2009 Telluride conference. To better understand these results, 21 additional sets of predictions were performed with the same program, varying the internal dielectric, reference pK(a), partial charge set, and dielectric boundary. The internal dielectric (ε(p)) and dielectric boundary were the two most important factors contributing to the quality of the predictions.

What do we know?: simple statistical techniques that help.

An understanding of simple statistical techniques is invaluable in science and in life. Despite this, and despite the sophistication of many concerning the methods and algorithms of molecular modeling, statistical analysis is usually rare and often uncompelling. I present here some basic approaches that have proved useful in my own work, along with examples drawn from the field.

Can we share questions? Performance of questions from different question banks in a single medical school.

Background: To use progress testing, a large bank of questions is required, particularly when planning to deliver tests over a long period of time. The questions need not only to be of good quality but also balanced in subject coverage across the curriculum to allow appropriate sampling. Hence as well as creating its own questions, an institution could share questions.

The SAMPL2 blind prediction challenge: introduction and overview.

The interactions between a molecule and the aqueous environment underpin any process that occurs in solution, from simple chemical reactions to protein-ligand binding to protein aggregation. Fundamental measures of the interaction between molecule and aqueous phase, such as the transfer energy between gas phase and water or the energetic difference between two tautomers of a molecule in solution, remain nontrivial to predict accurately using current computational methods. SAMPL2 represents the third annual blind prediction of transfer energies, and the first time tautomer ratios were included in the challenge.

Analysis of SM8 and Zap TK calculations and their geometric sensitivity.

A prospective study of aqueous solvation energies was done using the SM8 and Zap TK models for a variety of geometries. CM4M charges calculated with M06 and M06-2X were found to yield similar results for the SM8 model. Zap TK calculations were primarily done with AM1BCC charges but limited attempts to use charges derived from DFT showed promise.

SAMPL2 and continuum modeling.

An account is given of our contributions to the SAMPL2 challenge for vacuum-water transfer energies. These contributions include different charge sets and radii used with Poisson-Boltzmann continuum theory applied to a single low-energy conformation. A rationale for this approach is given, including a summary of what we have learnt over previous SAMPL events.

Molecular shape and medicinal chemistry: a perspective.

The eight contributions here provide ample evidence that shape as a volume or as a surface is a vibrant and useful concept when applied to drug discovery. It provides a reliable scaffold for "decoration" with chemical intuition (or bias) for virtual screening and lead optimization but also has its unadorned uses, as in library design, ligand fitting, pose prediction, or active site description. Computing power has facilitated this evolution by allowing shape to be handled precisely without the need to reduce down to point descriptors or approximate metrics, and the diversity of resultant applications argues for this being an important step forward.

Using electronic polarization from the internal continuum (EPIC) for intermolecular interactions.

Recently, the vacuum-phase molecular polarizability tensor of various molecules has been accurately modeled (Truchon et al., J Chem Theory Comput 2008, 4, 1480) with an intramolecular continuum dielectric model. This preliminary study showed that electronic polarization can be accurately modeled when combined with appropriate dielectric constants and atomic radii.

The SAMP1 solvation challenge: further lessons regarding the pitfalls of parametrization.

This paper describes an investigation into the performance of different charges and radii with the Poisson-Boltzmann method for the calculation of vacuum-water transfer energies. The test set consisted of 63 drug-like molecules used in a blind-test challenge. The results are consistent with earlier reports, namely, that more physical charges perform better and that radii parametrization can both improve and also dramatically worsen results, with the latter suggesting a failure to capture all of the basic physics of solvation.