A frequent problem in computational modeling is the interconversion of chemical structures between different formats. While standard interchange formats exist (for example, Chemical Markup Language) and de facto standards have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chemistry data, differences in the data stored by different formats (0D versus 3D, for example), and competition between software along with a lack of vendor-neutral formats. We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks the many languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chemical and molecular data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion. Open Babel presents a solution to the proliferation of multiple chemical file formats. In addition, it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chemical data in areas such as organic chemistry, drug design, materials science, and computational chemistry. It is freely available under an open-source license from http://openbabel.org
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Open Babel: An open chemical toolbox

Border Gateway Protocol (BGP) is the protocol backing the core routing decisions on the Internet. It maintains a table of IP networks or 'prefixes' which designate network reachability among autonomous systems (AS). Point of concern in BGP is its lack of effective security measures which makes Internet vulnerable to different forms of attacks. Many solutions have been proposed till date to combat BGP security issues but not a single one is deployable in practical scenario. Any security proposal with optimal solution should offer adequate security functions, performance overhead and deployment cost. This paper critically analyzes the deployment issues of best three proposals considering trade-off between security functions and performance overhead.

Comparative analysis of

ZINC is a free public resource for ligand discovery. The database contains over twenty million commercially available molecules in biologically relevant representations that may be downloaded in popular ready-to-dock formats and subsets. The Web site also enables searches by structure, biological activity, physical property, vendor, catalog number, name, and CAS number. Small custom subsets may be created, edited, shared, docked, downloaded, and conveyed to a vendor for purchase. The database is maintained and curated for a high purchasing success rate and is freely available at zinc.docking.org.

ZINC: A Free Tool to Discover Chemistry for Biology

Model fitting is an important part of all sciences that use quantitative measurements. Experimenters often explore the relationships between measures. Two subclasses of relationship problems are as follows: • Correlation problems: those in which we have a collection of measures, all of interest in their own right, and wish to see how and how strongly they are related. • Regression problems : those in which one of the measures, the dependent Variable, is of special interest, and we wish to explore its relationship with the other variables. These other variables may be called the independent Variables, the predictor Variables, or the coVariates. The dependent variable may be a continuous numeric measure such as a boiling point or a categorical measure such as a classification into mutagenic and nonmutagenic. We should emphasize that using the words ‘correlation problem’ and ‘regression problem’ is not meant to tie these problems to any particular statistical methodology. Having a ‘correlation problem’ does not limit us to conventional Pearson correlation coefficients. Log-linear models, for example, measure the relationship between categorical variables in multiway contingency tables. Similarly, multiple linear regression is a methodology useful for regression problems, but so also are nonlinear regression, neural nets, recursive partitioning and k-nearest neighbors, logistic regression, support vector machines and discriminant analysis, to mention a few. All of these methods aim to quantify the relationship between the predictors and the dependent variable. We will use the term ‘regression problem’ in this conceptual form and, when we want to specialize to multiple linear regression using ordinary least squares, will describe it as ‘OLS regression’. Our focus is on regression problems. We will use y as shorthand for the dependent variable and x for the collection of predictors available. There are two distinct primary settings in which we might want to do a regression study: • Prediction problems:We may want to make predictions of y for future cases where we know x but do not knowy. This for example is the problem faced with the Toxic Substances Control Act (TSCA) list. This list contains many tens of thousands of compounds, and there is a need to identify those on the list that are potentially harmful. Only a small fraction of the list however has any measured biological properties, but all of them can be characterized by chemical descriptors with relative ease. Using quantitative structure-activity relationships (QSARs) fitted to this small fraction to predict the toxicities of the much larger collection is a potentially cost-effective way to try to sort the TSCA compounds by their potential for harm. Later, we will use a data set for predicting the boiling point of a set of compounds on the TSCA list from some molecular descriptors. • Effect quantification:We may want to gain an understanding of how the predictors enter into the relationship that predicts y. We do not necessarily have candidate future unknowns that we want to predict, we simply want to know how each predictor drives the distribution of y. This is the setting seen in drug discovery, where the biological activity y of each in a collection of compounds is measured, along with molecular descriptors x. Finding out which descriptors x are associated with high and which with low biological activity leads to a recipe for new compounds which are high in the features associated positively with activity and low in those associated with inactivity or with adverse side effects. These two objectives are not always best served by the same approaches. ‘Feature selection’ skeeping those features associated withy and ignoring those not associated with y is very commonly a part of an analysis meant for effect quantification but is not necessarily helpful if the objective is prediction of future unknowns. For prediction, methods such as partial least squares (PLS) and ridge regression (RR) that retain all features but rein in their contributions are often found to be more effective than those relying on feature selection. What Is Overfitting? Occam’s Razor, or the principle of parsimony, calls for using models and procedures that contain all that is necessary for the modeling but nothing more. For example, if a regression model with 2 predictors is enough to explainy, then no more than these two predictors should be used. Going further, if the relationship can be captured by a linear function in these two predictors (which is described by 3 numbers sthe intercept and two slopes), then using a quadratic violates parsimony. Overfitting is the use of models or procedures that violate parsimonysthat is, that include more terms than are necessary or use more complicated approaches than are necessary. It is helpful to distinguish two types of overfitting: • Using a model that is more flexible than it needs to be. For example, a neural net is able to accommodate some curvilinear relationships and so is more flexible than a simple linear regression. But if it is used on a data set that conforms to the linear model, it will add a level of complexity without * Corresponding author e-mail: doug@stat.umn.edu. 1 J. Chem. Inf. Comput. Sci. 2004,44, 1-12

The problem of overfitting.

The authors describe the development and testing of a semiempirical free energy force field for use in AutoDock4 and similar grid-based docking methods. The force field is based on a comprehensive thermodynamic model that allows incorporation of intramolecular energies into the predicted free energy of binding. It also incorporates a charge-based method for evaluation of desolvation designed to use a typical set of atom types. The method has been calibrated on a set of 188 diverse protein-ligand complexes of known structure and binding energy, and tested on a set of 100 complexes of ligands with retroviral proteases. The force field shows improvement in redocking simulations over the previous AutoDock3 force field.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcc.20634

A semiempirical free energy force field with charge-based desolvation.

Internet technology offers an excellent opportunity for the development of tools by the cooperative effort of various groups and institutions. We have developed a multi-platform software system, Virtual Computational Chemistry Laboratory, http://www.vcclab.org, allowing the computational chemist to perform a comprehensive series of molecular indices/properties calculations and data analysis. The implemented software is based on a three-tier architecture that is one of the standard technologies to provide client-server services on the Internet. The developed software includes several popular programs, including the indices generation program, DRAGON, a 3D structure generator, CORINA, a program to predict lipophilicity and aqueous solubility of chemicals, ALOGPS and others. All these programs are running at the host institutes located in five countries over Europe. In this article we review the main features and statistics of the developed system that can be used as a prototype for academic and industry models.

Virtual computational chemistry laboratory - design and description

The application of feed forward back propagation artificial neural networks with one hidden layer (ANN) to perform the equivalent of multiple linear regression (MLR) has been examined using artificial structured data sets and real literature data. The predictive ability of the networks has been estimated using a training/ test set protocol. The results have shown advantages of ANN over MLR analysis. The ANNs do not require high order terms or indicator variables to establish complex structure-activity relationships. Overfitting does not have any influence on network prediction ability when overtraining is avoided by cross-validation. Application of ANN ensembles has allowed the avoidance of chance correlations and satisfactory predictions of new data have been obtained for a wide range of numbers of neurons in the hidden layer.

Neural network studies. 1. Comparison of overfitting and overtraining

INTRODUCTION Predicting Chemical Toxicity and Fate in Humans and the Environment - An Introduction METHODOLOGY Toxicity Data Sources Calculation of Physicochemical Properties Good Practice in Physicochemical Property Prediction Whole Molecule and Atom Based Topological Descriptors Quantum Chemical Descriptors in Structure-Activity Relationships - Calculation, Interpretation and comparison of Methods Building QSAR Models - A Practical Guide QSARs FOR HUMAN HEALTH ENDPOINTS Prediction of Human Health Endpoints: Mutagenicity and Carcinogenicity The Use of Expert Systems for Toxicity Prediction - Illustrated with Reference to the DEREK Program Computer-Based Methods for the Prediction of Chemical Metabolism and Biotransformation within Biological Organisms Prediction of Pharmacokinetic Parameters in Drug Design and Toxicology QSARs FOR ENVIRONMENTAL TOXICITY AND FATE An Exercise in External Validation: The Benzene Response-Surface Model for Tetrahymena Toxicity Receptor-Mediated Toxicity: QSARs for Oestrogen Receptor Binding and Priority Setting of Potential Oestrogenic Endocrine Disruptors Prediction of Persistence QSAR Modelling of Bioaccumulation QSAR Modelling of Soil Sorption Application of Catabolic-Based Biosensors to Develop QSARs for Degradation APPLICATION The Tiered Approach to Toxicity Assessment Based on the Integrated Use of Alternative (Non-Animal) Tests The Use of Quantitative Structure-Activity Relationships and Expert Systems to Predict Toxicity by Governmental Regulatory Agencies A Framework for Promoting the Acceptance and Regulatory Use of (Quantitative) Structure-Activity Relationships.

Predicting Chemical Toxicity and Fate

An unsupervised learning method is proposed for variable selection and its performance assessed using three typical QSAR data sets. The aims of this procedure are to generate a subset of descriptors from any given data set in which the resultant variables are relevant, redundancy is eliminated, and multicollinearity is reduced. Continuum regression, an algorithm encompassing ordinary least squares regression, regression on principal components, and partial least squares regression, was used to construct models from the selected variables. The variable selection routine is shown to produce simple, robust, and easily interpreted models for the chosen data sets.

Unsupervised Forward Selection: A Method for Eliminating Redundant Variables

The origins and operation of artificial neural networks are briefly described and their early application to data modelling in drug design is reviewed. Four problems in the use of neural networks in data modelling are discussed, namely overfitting, chance effects, overtraining and interpretation, and examples are given of the means by which the first three of these may be avoided. The use of neural networks as a variable selection tool is shown and the advantage of networks as a nonlinear data modelling device is discussed. The display of multivariate data in two dimensions employing a neural network is illustrated using experimental and theoretical data for a set of charge transfer complexes.

David J. Livingstone

Papers

Virtual computational chemistry laboratory - design and description

Neural network studies. 1. Comparison of overfitting and overtraining

Predicting Chemical Toxicity and Fate

Unsupervised Forward Selection: A Method for Eliminating Redundant Variables

Data modelling with neural networks: Advantages and limitations