A probabilistic approach to classifying metabolic stability.

Abstract:

:Metabolic stability is an important property of drug molecules that should-optimally-be taken into account early on in the drug design process. Along with numerous medium- or high-throughput assays being implemented in early drug discovery, a prediction tool for this property could be of high value. However, metabolic stability is inherently difficult to predict, and no commercial tools are available for this purpose. In this work, we present a machine learning approach to predicting metabolic stability that is tailored to compounds from the drug development process at Bayer Schering Pharma. For four different in vitro assays, we develop Bayesian classification models to predict the probability of a compound being metabolically stable. The chosen approach implicitly takes the "domain of applicability" into account. The developed models were validated on recent project data at Bayer Schering Pharma, showing that the predictions are highly accurate and the domain of applicability is estimated correctly. Furthermore, we evaluate the modeling method on a set of publicly available data.

journal_name

J Chem Inf Model

authors

Schwaighofer A,Schroeter T,Mika S,Hansen K,Ter Laak A,Lienau P,Reichel A,Heinrich N,Müller KR

doi

10.1021/ci700142c

subject

Has Abstract

pub_date

2008-04-01 00:00:00

pages

785-96

issue

4

eissn

1549-9596

issn

1549-960X

journal_volume

48

pub_type

杂志文章
  • ReFlex3D: Refined Flexible Alignment of Molecules Using Shape and Electrostatics.

    abstract::We present an algorithm, ReFlex3D, for the refinement of flexible molecular alignments based on their three-dimensional shape and electrostatic properties. The algorithm is designed to be used with fast conformer generators to refine an initial overlay between two molecules and thus to obtain improved overlaps as judg...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.7b00618

    authors: Schmidt TC,Cosgrove DA,Boström J

    更新日期:2018-04-23 00:00:00

  • New fragment weighting scheme for the Bayesian inference network in ligand-based virtual screening.

    abstract::Many of the conventional similarity methods assume that molecular fragments that do not relate to biological activity carry the same weight as the important ones. One possible approach to this problem is to use the Bayesian inference network (BIN), which models molecules and reference structures as probabilistic infer...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci100232h

    authors: Abdo A,Salim N

    更新日期:2011-01-24 00:00:00

  • FORTRAN interface for code interoperability in quantum chemistry: the Q5Cost library.

    abstract::Ab initio quantum-chemistry programs produce and use large amounts of data, which are usually stored on disk in the form of binary files. A FORTRAN library, named Q5Cost, has been designed and implemented in order to allow the storage of these data sets in a special data format built with the HDF5 technology. This dat...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci7000567

    authors: Borini S,Monari A,Rossi E,Tajti A,Angeli C,Bendazzoli GL,Cimiraglia R,Emerson A,Evangelisti S,Maynau D,Sanchez-Marin J,Szalay PG

    更新日期:2007-05-01 00:00:00

  • In Silico Study of Membrane Lipid Composition Regulating Conformation and Hydration of Influenza Virus B M2 Channel.

    abstract::The proton conduction of transmembrane influenza virus B M2 (BM2) proton channel is possibly mediated by the membrane environment, but the detailed molecular mechanism is challenging to determine. In this work, how membrane lipid composition regulates the conformation and hydration of BM2 channel is elucidated in sili...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.0c00329

    authors: Zhang Y,Zhang HX,Zheng QC

    更新日期:2020-07-27 00:00:00

  • Prediction of cytochrome P450 xenobiotic metabolism: tethered docking and reactivity derived from ligand molecular orbital analysis.

    abstract::Metabolism of xenobiotic and endogenous compounds is frequently complex, not completely elucidated, and therefore often ambiguous. The prediction of sites of metabolism (SoM) can be particularly helpful as a first step toward the identification of metabolites, a process especially relevant to drug discovery. This pape...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci400058s

    authors: Tyzack JD,Williamson MJ,Torella R,Glen RC

    更新日期:2013-06-24 00:00:00

  • Comments on the article "Evaluation of pK(a) estimation methods on 211 druglike compounds".

    abstract::The recent article "Evaluation of pK(a) Estimation Methods on 211 Druglike Compounds" ( Manchester, J.; et al. J. Chem Inf. Model. 2010, 50, 565-571 ) reports poor results for the program Epik. Here, we highlight likely sources for the poor performance and describe work done to improve the performance. Running Epik in...

    journal_title:Journal of chemical information and modeling

    pub_type: 评论,杂志文章

    doi:10.1021/ci100332m

    authors: Shelley JC,Calkins D,Sullivan AP

    更新日期:2011-01-24 00:00:00

  • Viscosity Prediction of Lubricants by a General Feed-Forward Neural Network.

    abstract::Modern industrial lubricants are often blended with an assortment of chemical additives to improve the performance of the base stock. Machine learning-based predictive models allow fast and veracious derivation of material properties and facilitate novel and innovative material designs. In this study, we outline the d...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.9b01068

    authors: Loh GC,Lee HC,Tee XY,Chow PS,Zheng JW

    更新日期:2020-03-23 00:00:00

  • Toward high throughput 3D virtual screening using spherical harmonic surface representations.

    abstract::Searching chemical databases for possible drug leads is often one of the main activities conducted during the early stages of a drug development project. This article shows that spherical harmonic molecular shape representations provide a powerful way to search and cluster small-molecule databases rapidly and accurate...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci7001507

    authors: Mavridis L,Hudson BD,Ritchie DW

    更新日期:2007-09-01 00:00:00

  • Evaluating Unexpectedly Short Non-covalent Distances in X-ray Crystal Structures of Proteins with Electronic Structure Analysis.

    abstract::We investigate unexpectedly short non-covalent distances (<85% of the sum of van der Waals radii) in X-ray crystal structures of proteins. We curate over 11 000 high-quality protein crystal structures and an ultra-high-resolution (1.2 Å or better) subset containing >900 structures. Although our non-covalent distance c...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.9b00144

    authors: Qi HW,Kulik HJ

    更新日期:2019-05-28 00:00:00

  • Transplant-insert-constrain-relax-assemble (TICRA): protein-ligand complex structure modeling and application to kinases.

    abstract::We introduce TICRA (transplant-insert-constrain-relax-assemble), a method for modeling the structure of unknown protein-ligand complexes using the X-ray crystal structures of homologous proteins and ligands with known activity. We present results from modeling the structures of protein kinase-inhibitor complexes using...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci100256u

    authors: Meshkat S,Klon AE,Zou J,Wiseman JS,Konteatis Z

    更新日期:2011-01-24 00:00:00

  • Novel inhibitors of human histone deacetylase (HDAC) identified by QSAR modeling of known inhibitors, virtual screening, and experimental validation.

    abstract::Inhibitors of histone deacetylases (HDACIs) have emerged as a new class of drugs for the treatment of human cancers and other diseases because of their effects on cell growth, differentiation, and apoptosis. In this study we have developed several quantitative structure-activity relationship (QSAR) models for 59 chemi...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci800366f

    authors: Tang H,Wang XS,Huang XP,Roth BL,Butler KV,Kozikowski AP,Jung M,Tropsha A

    更新日期:2009-02-01 00:00:00

  • 3D QSAR methods: Phase and Catalyst compared.

    abstract::The programs Phase and Catalyst HypoGen are compared for their performance in determining three-dimensional quantitative structure-activity relationships. Eight sets of compounds with measured activity were collected from the public literature and partitioned into suitable training and test sets by an automated proced...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci7000082

    authors: Evans DA,Doman TN,Thorner DA,Bodkin MJ

    更新日期:2007-05-01 00:00:00

  • An Efficient Lossless Compression Algorithm for Trajectories of Atom Positions and Volumetric Data.

    abstract::We present our newly developed and highly efficient lossless compression algorithm for trajectories of atom positions and volumetric data. The algorithm is designed as a two-step approach. In the first step, efficient polynomial extrapolation schemes reduce the information entropy of the data by exploiting both spatia...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.8b00501

    authors: Brehm M,Thomas M

    更新日期:2018-10-22 00:00:00

  • Computational Insight Into the Mechanism of SARS-CoV-2 Membrane Fusion.

    abstract::Membrane fusion, a key step in the early stages of virus propagation, allows the release of the viral genome in the host cell cytoplasm. The process is initiated by fusion peptides that are small, hydrophobic components of viral membrane-embedded glycoproteins and are typically conserved within virus families. Here, w...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.0c01231

    authors: Borkotoky S,Dey D,Banerjee M

    更新日期:2021-01-25 00:00:00

  • CoMFA, CoMSIA, and molecular hologram QSAR studies of novel neuronal nAChRs ligands-open ring analogues of 3-pyridyl ether.

    abstract::3-Pyridyl ethers are excellent nAChRs ligands, which show high subtype selectivity and binding affinity to alpha4beta2 nAChR. Although the quantitative structure-activity relationship (QSAR) of nAChRs ligands has been widely investigated using various classes of compounds, the open ring analogues of 3-pyridyl ethers h...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci0498113

    authors: Zhang H,Li H,Liu C

    更新日期:2005-03-01 00:00:00

  • Underestimated Halogen Bonds Forming with Protein Backbone in Protein Data Bank.

    abstract::Halogen bonds (XBs) are attracting increasing attention in biological systems. Protein Data Bank (PDB) archives experimentally determined XBs in biological macromolecules. However, no software for structure refinement in X-ray crystallography takes into account XBs, which might result in the weakening or even vanishin...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.7b00235

    authors: Zhang Q,Xu Z,Shi J,Zhu W

    更新日期:2017-07-24 00:00:00

  • Perturbation-Theory and Machine Learning (PTML) Model for High-Throughput Screening of Parham Reactions: Experimental and Theoretical Studies.

    abstract::Machine learning (ML) algorithms are gaining importance in the processing of chemical information and modeling of chemical reactivity problems. In this work, we have developed a perturbation-theory and machine learning (PTML) model combining perturbation theory (PT) and ML algorithms for predicting the yield of a give...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.8b00286

    authors: Simón-Vidal L,García-Calvo O,Oteo U,Arrasate S,Lete E,Sotomayor N,González-Díaz H

    更新日期:2018-07-23 00:00:00

  • Synergistic use of compound properties and docking scores in neural network modeling of CYP2D6 binding: predicting affinity and conformational sampling.

    abstract::Cytochrome P450 2D6 (CYP2D6) is used to develop an approach for predicting affinity and relevant binding conformation(s) for highly flexible binding sites. The approach combines the use of docking scores and compound properties as attributes in building a neural network (NN) model. It begins by identifying segments of...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci600267k

    authors: Bazeley PS,Prithivi S,Struble CA,Povinelli RJ,Sem DS

    更新日期:2006-11-01 00:00:00

  • Modeling oral rat chronic toxicity.

    abstract::The chronic toxicity is fundamental for toxicological risk assessment, but its correlation with the chemical structures has been studied only little. This is partly due to the complexity of such an experimental test that embraces a plethora of different biological effects and mechanisms of action, making (Q)SAR studie...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci8001974

    authors: Mazzatorta P,Estevez MD,Coulet M,Schilter B

    更新日期:2008-10-01 00:00:00

  • Protein-protein binding site prediction by local structural alignment.

    abstract::Generalization of an earlier algorithm has led to the development of new local structural alignment algorithms for prediction of protein-protein binding sites. The algorithms use maximum cliques on protein graphs to define structurally similar protein regions. The search for structural neighbors in the new algorithms ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci100265x

    authors: Carl N,Konc J,Vehar B,Janezic D

    更新日期:2010-10-25 00:00:00

  • Cross-docking of inhibitors into CDK2 structures. 2.

    abstract::In the preceding paper (Duca, J. S.; Madison, V. S.; Voigt, J. H. J. Chem. Inf. Model. 2008, 48, 659-668), the accuracy of docking and affinity predictions of the Gold and Glide programs were investigated using single protein conformations spanning 150 CDK2/inhibitor crystallographic complexes. High docking accuracy w...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci700428d

    authors: Voigt JH,Elkin C,Madison VS,Duca JS

    更新日期:2008-03-01 00:00:00

  • Open Source Bayesian Models. 1. Application to ADME/Tox and Drug Discovery Datasets.

    abstract::On the order of hundreds of absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) models have been described in the literature in the past decade which are more often than not inaccessible to anyone but their authors. Public accessibility is also an issue with computational models for bioactivity, a...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.5b00143

    authors: Clark AM,Dole K,Coulon-Spektor A,McNutt A,Grass G,Freundlich JS,Reynolds RC,Ekins S

    更新日期:2015-06-22 00:00:00

  • Accurate Hit Estimation for Iterative Screening Using Venn-ABERS Predictors.

    abstract::Iterative screening has emerged as a promising approach to increase the efficiency of high-throughput screening (HTS) campaigns in drug discovery. By learning from a subset of the compound library, inferences on what compounds to screen next can be made by predictive models. One of the challenges of iterative screenin...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.8b00724

    authors: Buendia R,Kogej T,Engkvist O,Carlsson L,Linusson H,Johansson U,Toccaceli P,Ahlberg E

    更新日期:2019-03-25 00:00:00

  • In Silico Classifiers for the Assessment of Drug Proarrhythmicity.

    abstract::Drug-induced torsade de pointes (TdP) is a life-threatening ventricular arrhythmia responsible for the withdrawal of many drugs from the market. Although currently used TdP risk-assessment methods are effective, they are expensive and prone to produce false positives. In recent years, in silico cardiac simulations hav...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.0c00201

    authors: Llopis-Lorente J,Gomis-Tena J,Cano J,Romero L,Saiz J,Trenor B

    更新日期:2020-10-26 00:00:00

  • Determining the validity of a QSAR model--a classification approach.

    abstract::The determination of the validity of a QSAR model when applied to new compounds is an important concern in the field of QSAR and QSPR modeling. Various scoring techniques can be applied to specific types of models. We present a technique with which we can state whether a new compound will be well predicted by a previo...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci0497511

    authors: Guha R,Jurs PC

    更新日期:2005-01-01 00:00:00

  • Growth of ligand-target interaction data in ChEMBL is associated with increasing and activity measurement-dependent compound promiscuity.

    abstract::Compounds with high-confidence target annotations and activity measurements in the original and current release of the ChEMBL database have been compared to better understand how the growth of compound activity data might influence the spectrum of ligand-target interactions and the degree of target promiscuity among a...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci3003304

    authors: Hu Y,Bajorath J

    更新日期:2012-10-22 00:00:00

  • Simulation of 2D NMR Spectra of Carbohydrates Using GODESS Software.

    abstract::Glycan Optimized Dual Empirical Spectrum Simulation (GODESS) is a web service, which has been recently shown to be one of the most accurate tools for simulation of (1)H and (13)C 1D NMR spectra of natural carbohydrates and their derivatives. The new version of GODESS supports visualization of the simulated (1)H and (1...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.6b00083

    authors: Kapaev RR,Toukach PV

    更新日期:2016-06-27 00:00:00

  • L-arginine binding to human inducible nitric oxide synthase: an antisymmetric funnel route toward isoform-specific inhibitors?

    abstract::Nitric oxide (NO) is an important signaling molecule produced by a family of enzymes called nitric oxide synthases (NOS). Because NO is involved in various pathological conditions, the development of potent and isoform-selective NOS inhibitors is an important challenge. In the present study, the dimer of oxygenase dom...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci100422v

    authors: Floquet N,Hernandez JF,Boucher JL,Martinez J

    更新日期:2011-06-27 00:00:00

  • In silico prediction of aqueous solubility: the solubility challenge.

    abstract::The dissolution of a chemical into water is a process fundamental to both chemistry and biology. The persistence of a chemical within the environment and the effects of a chemical within the body are dependent primarily upon aqueous solubility. With the well-documented limitations hindering the accurate experimental d...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci900286s

    authors: Hewitt M,Cronin MT,Enoch SJ,Madden JC,Roberts DW,Dearden JC

    更新日期:2009-11-01 00:00:00

  • Chemoinformatics-based classification of prohibited substances employed for doping in sport.

    abstract::Representative molecules from 10 classes of prohibited substances were taken from the World Anti-Doping Agency (WADA) list, augmented by molecules from corresponding activity classes found in the MDDR database. Together with some explicitly allowed compounds, these formed a set of 5245 molecules. Five types of fingerp...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci0601160

    authors: Cannon EO,Bender A,Palmer DS,Mitchell JB

    更新日期:2006-11-01 00:00:00