Abstract:
:Nonalcoholic hepatic steatosis is a worldwide epidemiological concern since it is among the most prominent hepatic diseases. Indeed, research in toxicology and epidemiology has gathered evidence that exposure to endocrine disruptors can perturb cellular homeostasis and cause this disease. Therefore, assessing the likelihood of a chemical to trigger hepatic steatosis is a matter of the utmost importance. However, systematic in vivo testing of all the chemicals humans are exposed to is not feasible for ethical and economical reasons. In this context, predicting the molecular initiating events (MIE) leading to hepatic steatosis by QSAR modeling is an issue of practical relevance in modern toxicology. In this article, we present QSAR models based on random forest classifiers and DRAGON molecular descriptors for the prediction of in vitro assays that are relevant to MIEs leading to hepatic steatosis. These assays were provided by the ToxCast program and proved to be predictive for the detection of chemical-induced steatosis. During the modeling process, special attention was paid to chemical and toxicological data curation. We adopted two modeling strategies (undersampling and balanced random forests) to develop robust QSAR models from unbalanced data sets. The two modeling approaches gave similar results in terms of predictivity, and most of the models satisfy a minimum percentage of correctly predicted chemicals equal to 75%. Finally, and most importantly, the developed models proved to be useful as an effective in silico screening test for hepatic steatosis.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Gadaleta D,Manganelli S,Roncaglioni A,Toma C,Benfenati E,Mombelli Edoi
10.1021/acs.jcim.8b00297subject
Has Abstractpub_date
2018-08-27 00:00:00pages
1501-1517issue
8eissn
1549-9596issn
1549-960Xjournal_volume
58pub_type
杂志文章abstract::The roles of chemical compounds in biological systems are now systematically analyzed by high-throughput experimental technologies. To automate the processing and interpretation of large-scale data it is necessary to develop bioinformatics methods to extract information from the chemical structures of these small mole...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci700006f
更新日期:2007-07-01 00:00:00
abstract::The possibility of improving the predictive ability of comparative molecular field analysis (CoMFA) by settings optimization has been evaluated to show that CoMFA predictive ability can be improved. Ten different CoMFA settings are evaluated, producing a total of 6120 models. This method has been applied to nine diffe...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci049612j
更新日期:2006-01-01 00:00:00
abstract::Side-chain modeling is critical for protein structure prediction since the uniqueness of the protein structure is largely determined by its side-chain packing conformation. In this paper, differing from most approaches that rely on rotamer library sampling, we first propose a novel side-chain rotamer prediction method...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00951
更新日期:2020-12-28 00:00:00
abstract::The emergence of a large amount of pharmacological, genomic, and network knowledge data provides new challenges and opportunities for drug discovery and development. Identification of real small-molecule drug (SM)-miRNA associations is not only important in the development of effective drug repositioning but also cruc...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00244
更新日期:2020-08-24 00:00:00
abstract::Determination of structural similarities between protein binding pockets is an important challenge in in silico drug design. It can help to understand selectivity considerations, predict unexpected ligand cross-reactivity, and support the putative annotation of function to orphan proteins. To this end, Cavbase was dev...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci5005898
更新日期:2015-01-26 00:00:00
abstract::Development of accurate force field parameters for molecular ions in the context of a polarizable energy function based on the classical Drude oscillator is a crucial step toward an accurate polarizable model for modeling and simulations of biological macromolecules. Toward this goal we have undertaken a hierarchical ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00132
更新日期:2018-05-29 00:00:00
abstract::Umami or the taste of monosodium glutamate represents one of the major attractive taste modalities in humans. Therefore, knowledge about biophysical and biochemical properties of the umami taste is important for both scientific research and the food industry. Experimental approaches for predicting umami peptides are l...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00707
更新日期:2020-12-28 00:00:00
abstract::We report the synthesis and a study of the structure-activity relationships of a new series of diarylhydrazides as potential selective non-ligand binding pocket androgen receptor antagonists. Their biological activity as antiandrogens in the context of the development of treatments for castration resistant prostate ca...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci400189m
更新日期:2013-08-26 00:00:00
abstract::Molecular channel exploration perseveres to be the prominent solution for eliciting structure and accessibility of active site and other internal spaces of macromolecules. The volume and silhouette characterization of these channels provides answers for the issues of substrate access and ligand swapping between the ob...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci200584f
更新日期:2012-02-27 00:00:00
abstract::Most drugs exert their effects via multitarget interactions, as hypothesized by polypharmacology. While these multitarget interactions are responsible for the clinical effect profiles of drugs, current methods have failed to uncover the complex relationships between them. Here, we introduce an approach which is able t...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci2002022
更新日期:2012-01-23 00:00:00
abstract::G-protein coupled receptors (GPCRs) are highly relevant drug targets. Four GPCRs with known crystal structure were analyzed with docking (AutoDock4) and postdocking (MM-PBSA) in order to evaluate the ability to recognize known antagonists from a larger database of molecular decoys and to predict correct binding modes....
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci4000745
更新日期:2013-04-22 00:00:00
abstract::A generic chemical transformation may often be achieved under various synthetic conditions. However, for any specific reagents, only one or a few among the reported synthetic protocols may be successful. For example, Michael β-addition reactions may proceed under different choices of solvent (e.g., hydrophobic, aproti...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci500698a
更新日期:2015-02-23 00:00:00
abstract::This article presents the computation of both inter- and intramolecular hydrogen bond strengths from first-principles. Quantum chemical calculations conducted at the dispersion-corrected density functional theory level including free energy and solvation contributions are conducted for (i) one-to-one hydrogen-bonded c...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00132
更新日期:2019-09-23 00:00:00
abstract::We introduce SARANEA, an open-source Java application for interactive exploration of structure-activity relationship (SAR) and structure-selectivity relationship (SSR) information in compound sets of any source. SARANEA integrates various SAR and SSR analysis functions and utilizes a network-like similarity graph data...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci900416a
更新日期:2010-01-01 00:00:00
abstract::Physicochemical atomic stereodescriptors (PAS) were implemented that represent the chirality of an atomic chiral center on the basis of empirical physicochemical properties of the ligands. The ligands are ranked according to a specific property, and the chiral center takes an S/R-like descriptor relative to that prope...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci600235w
更新日期:2006-11-01 00:00:00
abstract::Our recent studies show that the single Tyr residue in the sequence of amyloid-β42 (Aβ42) is reactive toward various ligands, including metals and adenosine trisphospate (see: Coskuner , O. J. Biol. Inorg. Chem. 2016 , 21 , 957 - 973 and Coskuner , O. ; Murray , I. V. J. J. Alzheimer's Dis. 2014 , 41 , 561 - 574 ). Ho...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.6b00761
更新日期:2017-06-26 00:00:00
abstract::This paper introduces the concept of an isomer network based on the reaction step counts between pairs of isomers as an alternative means to view and analyze isomer space. The computation of isomer networks is computationally expensive with respect to both run time and memory. Accordingly, this paper focuses on the de...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci4005173
更新日期:2014-01-27 00:00:00
abstract::Mapping the chemical space of small organic molecules is approached from a theoretical graph theory viewpoint, in an effort to begin the systematic exploration of molecular topologies. We present an algorithm for exhaustive generation of scaffold topologies with up to eight rings and an efficient comparison method for...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci7003412
更新日期:2008-07-01 00:00:00
abstract::We report a novel method called ADAN (Applicability Domain ANalysis) for assessing the reliability of drug property predictions obtained by in silico methods. The assessment provided by ADAN is based on the comparison of the query compound with the training set, using six diverse similarity criteria. For every criteri...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci500172z
更新日期:2014-05-27 00:00:00
abstract::A homology model of the Arabidopsis thaliana UV resistance locus 8 (UVR8) protein is presented herein, showing a seven-bladed β-propeller conformation similar to the globular structure of RCC1. The UVR8 amino acid sequence contains a very high amount of conserved tryptophans, and the homology model shows that seven of...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci200017f
更新日期:2011-06-27 00:00:00
abstract::Protein-polysaccharide complexes constructed via self-assembly methods are often used to develop novel biomaterials for a wide range of applications in biomedicine, food, and biotechnology. The objective of this work was to investigate theoretically and to demonstrate via constant-pH Monte Carlo simulations that the c...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00814
更新日期:2020-02-24 00:00:00
abstract::Protein-protein interactions are central to many biological processes, from intracellular communication to cytoskeleton assembly, and therefore represent an important class of targets for new therapeutics. The most common secondary structure in natural proteins is an α-helix. Small molecules seem to be attractive cand...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci200424a
更新日期:2012-02-27 00:00:00
abstract::Herein we investigate whether QM/MM could prove useful as a tool to study the often subtle binding phenomena found within pharmaceutical drug discovery programs. The goal of this investigation is to determine whether it is possible to employ high level QM/MM calculations to answer specific questions around a binding e...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci800419j
更新日期:2009-03-01 00:00:00
abstract::Saturated acyclic alkanes show steric strain if they are highly branched and, in extreme cases, fall apart rapidly at room temperature. Consequently, attempts to count the number of isomeric forms for a given molecular formula that neglect this physical consideration will inevitably overestimate the size of the availa...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci700246b
更新日期:2007-11-01 00:00:00
abstract::The concept of chemoisosterism of protein environments is introduced as the complementary property to bioisosterism of chemical fragments. In the same way that two chemical fragments are considered bioisosteric if they can bind to the same protein environment, two protein environments will be considered chemoisosteric...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci3002974
更新日期:2013-02-25 00:00:00
abstract::Molecular fingerprints are widely used for similarity-based virtual screening in drug discovery projects. In this paper we discuss the performance and the complementarity of nine two-dimensional fingerprints (Daylight, Unity, AlFi, Hologram, CATS, TRUST, Molprint 2D, ChemGPS, and ALOGP) in retrieving active molecules ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci0504723
更新日期:2006-05-01 00:00:00
abstract::A kinetic, reactivity-binding model has been proposed to predict the regioselectivity of substrates meditated by the CYP1A2 enzyme, which is responsible for the metabolism of planar-conjugated compounds such as caffeine. This model consists of a docking simulation for binding energy and a semiempirical molecular orbit...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci800001m
更新日期:2008-05-01 00:00:00
abstract::As computational drug design becomes increasingly reliant on virtual screening and on high-throughput 3D modeling, the need for fast, robust, and reliable methods for sampling molecular conformations has become greater than ever. Furthermore, chemical novelty is at a premium, forcing medicinal chemists to explore more...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci900238a
更新日期:2009-10-01 00:00:00
abstract::We present an induced fit docking approach called Adaptive BP-Dock that integrates perturbation response scanning (PRS) with the flexible docking protocol of RosettaLigand in an adaptive manner. We first perturb the binding pocket residues of a receptor and obtain a new conformation based on the residue response fluct...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00587
更新日期:2016-04-25 00:00:00
abstract::Visualizing high-dimensional data by projecting them into a two- or three-dimensional space is a popular approach in many scientific fields, including computer-aided drug design and cheminformatics. In contrast, dimensionality reduction techniques have been far less explored for materials informatics. Nevertheless, si...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00552
更新日期:2018-12-24 00:00:00