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Journal of Computer-Aided Molecular Design

, Volume 32, Issue 4, pp 573–582 | Cite as

In-silico guided discovery of novel CCR9 antagonists

  • Xin Zhang
  • Jason B. Cross
  • Jan Romero
  • Alexander Heifetz
  • Eric Humphries
  • Katie Hall
  • Yuchuan Wu
  • Sabrina Stucka
  • Jing Zhang
  • Haoqun Chandonnet
  • Blaise Lippa
  • M. Dominic Ryan
  • J. Christian Baber
Article
  • 267 Downloads

Abstract

Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.

Keywords

CCR9 Virtual screening Data fusion Chemokine receptor antagonist 

Abbreviations

CCR9

CC Chemokine receptor 9

CCL25

CC Chemokine ligand 25

GPCR

G-Protein coupled receptor

HTS

High-throughput screen

LE

Ligand efficiency

PCA

Principal component analysis

SAR

Structure–activity relationship

Notes

Acknowledgements

The authors thank Rory Curtis for biology leadership, Evotec for development and execution of the high-throughput screen, and MultiSpan for running the primary calcium FLIPR assay.

Supplementary material

10822_2018_113_MOESM1_ESM.docx (756 kb)
Supplementary material 1 (DOCX 756 KB)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Xin Zhang
    • 1
  • Jason B. Cross
    • 1
  • Jan Romero
    • 1
  • Alexander Heifetz
    • 2
  • Eric Humphries
    • 1
  • Katie Hall
    • 1
  • Yuchuan Wu
    • 1
  • Sabrina Stucka
    • 1
  • Jing Zhang
    • 1
  • Haoqun Chandonnet
    • 1
  • Blaise Lippa
    • 1
  • M. Dominic Ryan
    • 1
  • J. Christian Baber
    • 1
  1. 1.Cubist PharmaceuticalsLexingtonUSA
  2. 2.Evotec (UK) Ltd.AbingdonUK

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