pkCSM: Predicting
Small-Molecule Pharmacokinetic and
Toxicity Properties Using Graph-Based Signatures

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Abstract

Drug development has a high attrition rate, with poor pharmacokinetic and safety properties a significant hurdle. Computational approaches may help minimize these risks. We have developed a novel approach (pkCSM) which uses graph-based signatures to develop predictive models of central ADMET properties for drug development. pkCSM performs as well or better than current methods. A freely accessible web server ( http://structure.bioc.cam.ac.uk/pkcsm), which retains no information submitted to it, provides an integrated platform to rapidly evaluate pharmacokinetic and toxicity properties.

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Most cited references 38

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The meaning and use of the area under a receiver operating characteristic (ROC) curve.

J A Hanley, B J McNeil, Marnix van Holsbeeck (1982)

A representation and interpretation of the area under a receiver operating characteristic (ROC) curve obtained by the "rating" method, or by mathematical predictions based on patient characteristics, is presented. It is shown that in such a setting the area represents the probability that a randomly chosen diseased subject is (correctly) rated or ranked with greater suspicion than a randomly chosen non-diseased subject. Moreover, this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic. These two relationships are exploited to (a) provide rapid closed-form expressions for the approximate magnitude of the sampling variability, i.e., standard error that one uses to accompany the area under a smoothed ROC curve, (b) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area, and (c) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques.

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DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach

Douglas Pires, David B. Ascher, Tom Blundell (2014)

Cancer genome and other sequencing initiatives are generating extensive data on non-synonymous single nucleotide polymorphisms (nsSNPs) in human and other genomes. In order to understand the impacts of nsSNPs on the structure and function of the proteome, as well as to guide protein engineering, accurate in silicomethodologies are required to study and predict their effects on protein stability. Despite the diversity of available computational methods in the literature, none has proven accurate and dependable on its own under all scenarios where mutation analysis is required. Here we present DUET, a web server for an integrated computational approach to study missense mutations in proteins. DUET consolidates two complementary approaches (mCSM and SDM) in a consensus prediction, obtained by combining the results of the separate methods in an optimized predictor using Support Vector Machines (SVM). We demonstrate that the proposed method improves overall accuracy of the predictions in comparison with either method individually and performs as well as or better than similar methods. The DUET web server is freely and openly available at http://structure.bioc.cam.ac.uk/duet.

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Physiochemical drug properties associated with in vivo toxicological outcomes.

Jason Hughes, Julian Blagg, David A. Price … (2008)

Relationships between physicochemical drug properties and toxicity were inferred from a data set consisting of animal in vivo toleration (IVT) studies on 245 preclinical Pfizer compounds; an increased likelihood of toxic events was found for less polar, more lipophilic compounds. This trend held across a wide range of types of toxicity and across a broad swath of chemical space.

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Author and article information

Journal

Journal ID (nlm-ta): J Med Chem

Journal ID (iso-abbrev): J. Med. Chem

Journal ID (publisher-id): jm

Journal ID (coden): jmcmar

Title: Journal of Medicinal Chemistry

Publisher: American Chemical Society

ISSN (Print): 0022-2623

ISSN (Electronic): 1520-4804

Publication date (Electronic): 10 April 2015

Publication date (Print): 14 May 2015

Volume: 58

Issue: 9

Pages: 4066-4072

Affiliations

[† ]Department of Biochemistry, University of Cambridge , 80 Tennis Court Road, Sanger Building, Cambridge, Cambridgshire CB2 1GA, U.K.

[‡ ]Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz , Belo Horizonte 30190-002, Brazil

Author notes

[* ]For D.E.V.P.: phone, +44 1223766033; fax, +44 1223766002; E-mail, douglas.pires@ 123456cpqrr.fiocruz.br .

[* ]For D.B.A.: phone, +44 1223766033; fax, +44 1223766002; E-mail, dascher@ 123456svi.edu.au .

Article

DOI: 10.1021/acs.jmedchem.5b00104

PMC ID: 4434528

PubMed ID: 25860834

SO-VID: 7eed35fd-a794-4b07-abea-46bbd00fb34f

License:

This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

History

Date received : 20 January 2015

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document-id-new-14 jm-2015-00104e

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ScienceOpen disciplines: Pharmaceutical chemistry

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ScienceOpen disciplines: Pharmaceutical chemistry

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pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures

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Abstract

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Drug_transporters

Most cited references 38

The meaning and use of the area under a receiver operating characteristic (ROC) curve.

DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach

Physiochemical drug properties associated with in vivo toxicological outcomes.

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