Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study

Vibhu Jha, Salvatore Galati, Valerio Volpi, Lidia Ciccone, Filippo Minutolo, Flavio Rizzolio, Carlotta Granchi, Giulio Poli, Tiziano Tuccinardi

Research output: Contribution to journalArticlepeer-review


ATP citrate lyase (ACLY) is an important enzyme that catalyzes the conversion of citrate to acetyl-CoA in normal cells, facilitating the de novo fatty acid synthesis. Lipids and fatty acids were found to be accumulated in different types of tumors, such as brain, breast, rectal and ovarian cancer, representing a great source of energy for cancer cell growth and metabolism. Since ACLY-mediated conversion of citrate to acetyl-CoA constitutes the basis for fatty acid synthesis, ACLY seems to be quite an unexplored and promising therapeutic target for anticancer drug design. A pharmacophore-based virtual screening (VS) protocol with the aid of hierarchical docking, consensus docking (CD), molecular dynamics (MD) simulations and ligand-protein binding free energy calculations led to the identification of compound VS1, which showed a moderate but promising inhibitory activity, demonstrating to be 2.5 times more potent than reference inhibitor 2-hydroxycitrate. These results validate the reliability of our VS workflow and pave the way for the design of novel and more potent ACLY inhibitors. Communicated by Ramaswamy H. Sarma.

Original languageEnglish
JournalJournal of Biomolecular Structure and Dynamics
Publication statusAccepted/In press - 2020


  • ACLY
  • consensus docking
  • molecular dynamics
  • pharmacophore
  • virtual screening

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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