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Journal of Computer-Aided Molecular Design

, Volume 29, Issue 1, pp 59–66 | Cite as

A desirability function-based scoring scheme for selecting fragment-like class A aminergic GPCR ligands

  • Ádám A. Kelemen
  • György G. Ferenczy
  • György M. Keserű
Article

Abstract

A physicochemical property-based desirability scoring scheme for fragment-based drug discovery was developed for class A aminergic GPCR targeted fragment libraries. Physicochemical property distributions of known aminergic GPCR-active fragments from the ChEMBL database were examined and used for a desirability function-based score. Property-distributions such as log D (at pH 7.4), PSA, pKa (strongest basic center), number of nitrogen atoms, number of oxygen atoms, and the number of rotatable bonds were combined into a desirability score (FrAGS). The validation of the scoring scheme was carried out using both public and proprietary experimental screening data. The scoring scheme is suitable for the design of aminergic GPCR targeted fragment libraries and might be useful for preprocessing fragments before structure based virtual or wet screening.

Keywords

G-protein coupled receptors Fragment-based drug discovery Desirability function Aminergic fragment library 

Abbreviations

FrAGS

Fragment Aminergic GPCR Score

GPCR

G-protein coupled receptor

PSA

Polar surface area

FBDD

Fragment-based drug discovery

HTS

High-throughput screening

FS

Fragment-screening

7TM

Seven-transmembrane

SILE

Size-independent ligand-efficiency

SMILES

Simplified molecular-input line-entry system

EF

Enrichment factor

TPR

True positive rate

TNR

True negative rate

FPR

False positive rate

FNR

False negative rate

ROC

Receiver operating characteristic

TAAR1

Trace-amine receptor subtype 1

5HT1

5-Hydroxy-tryptamine receptor subtype 1

Notes

Acknowledgments

We thank for Gedeon Richter Plc for providing GPCR-related fragment-screening and high-throughput screening data for the validation studies and particularly Márton Vass for helpful discussions.

Supplementary material

10822_2014_9804_MOESM1_ESM.pdf (758 kb)
Supplementary material 1 (PDF 758 kb)
10822_2014_9804_MOESM2_ESM.xlsx (28 kb)
Supplementary material 2 (XLSX 27 kb)
10822_2014_9804_MOESM3_ESM.xlsx (9 kb)
Supplementary material 3 (XLSX 9 kb)

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Ádám A. Kelemen
    • 1
  • György G. Ferenczy
    • 1
  • György M. Keserű
    • 1
  1. 1.Medicinal Chemistry Research Group, Research Centre for Natural SciencesHungarian Academy of SciencesBudapestHungary

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