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Autocorrelation descriptor improvements for QSAR: 2DA_Sign and 3DA_Sign

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Abstract

Quantitative structure–activity relationship (QSAR) is a branch of computer aided drug discovery that relates chemical structures to biological activity. Two well established and related QSAR descriptors are two- and three-dimensional autocorrelation (2DA and 3DA). These descriptors encode the relative position of atoms or atom properties by calculating the separation between atom pairs in terms of number of bonds (2DA) or Euclidean distance (3DA). The sums of all values computed for a given small molecule are collected in a histogram. Atom properties can be added with a coefficient that is the product of atom properties for each pair. This procedure can lead to information loss when signed atom properties are considered such as partial charge. For example, the product of two positive charges is indistinguishable from the product of two equivalent negative charges. In this paper, we present variations of 2DA and 3DA called 2DA_Sign and 3DA_Sign that avoid information loss by splitting unique sign pairs into individual histograms. We evaluate these variations with models trained on nine datasets spanning a range of drug target classes. Both 2DA_Sign and 3DA_Sign significantly increase model performance across all datasets when compared with traditional 2DA and 3DA. Lastly, we find that limiting 3DA_Sign to maximum atom pair distances of 6 Å instead of 12 Å further increases model performance, suggesting that conformational flexibility may hinder performance with longer 3DA descriptors. Consistent with this finding, limiting the number of bonds in 2DA_Sign from 11 to 5 fails to improve performance.

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Abbreviations

2DA:

2D autocorrelation

3DA:

3D autocorrelation

ANN:

Artificial neural network

BCL:

BioChemical library

CADD:

Computer aided drug discovery

GPCR:

G-protein coupled receptor

HTS:

High-throughput screen

LB-CADD:

Ligand-based CADD

logAUC:

Area under the logarithmic ROC curve

LOO:

Leave-one-out

QSAR:

Quantitative structure–activity relationship

RDF:

Radial distribution function

ROC:

Receiver operating characteristic

VDW:

Van der Waals

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Acknowledgments

Work in the Meiler laboratory is supported through NIH (R01 GM080403, R01 GM099842, R01 DK097376, R01 HL122010, R01 GM073151, U19 AI117905) and NSF (CHE 1305874).

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Authors and Affiliations

  1. Departments of Chemistry, Pharmacology, and Biomedical Informatics, Center for Structural Biology, Institute for Chemical Biology, Vanderbilt University, 7330 Stevenson Center, Station B 351822, Nashville, TN, 37235, USA

    Gregory Sliwoski, Jeffrey Mendenhall & Jens Meiler

  2. Institute of Biochemistry, Leipzig University, Brüderstraße 34, 04103, Leipzig, Germany

    Gregory Sliwoski

Authors
  1. Gregory Sliwoski
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  2. Jeffrey Mendenhall
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  3. Jens Meiler
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Correspondence to Jens Meiler.

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Sliwoski, G., Mendenhall, J. & Meiler, J. Autocorrelation descriptor improvements for QSAR: 2DA_Sign and 3DA_Sign. J Comput Aided Mol Des 30, 209–217 (2016). https://doi.org/10.1007/s10822-015-9893-9

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  • DOI: https://doi.org/10.1007/s10822-015-9893-9

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