Discovery of Chemical Scaffolds as Lysophosphatidic Acid Receptor 1 Antagonists: Virtual Screening, In Vitro Validation, and Molecular Dynamics Analysis

Lan Phuong Nguyen, Rasel Ahmed Khan, Soomin Kang, Hobin Lee, Jong Ik Hwang, Hong Rae Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Lysophosphatidic acid receptor 1 (LPAR1) is an emerging therapeutic target for numerous human diseases including fibrosis. However, the limited number of available core structures of LPAR1 antagonists has prompted the need for novel chemical templates. In this study, we conducted a high-throughput virtual screening to discover potential new scaffolds. We tested three existing crystal structures alongside an AlphaFold model to evaluate their suitability in structure-based virtual screening, finding that the crystal structures show superior performance compared with the predictive model. Furthermore, we also found that enhancing the precision in the screening process did not necessarily improve the enrichment of hits. From the screening campaign, we identified five structures that were validated using an LPAR1-dependent calcium flux assay. To gain a deeper insight into the protein-ligand interaction, we extensively analyzed the binding modes of these compounds using in silico techniques, laying the groundwork for the discovery of novel LPAR1 antagonists.

Original languageEnglish
Pages (from-to)40375-40386
Number of pages12
JournalACS Omega
Volume8
Issue number43
DOIs
Publication statusPublished - 2023 Oct 31

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering

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