TY - JOUR
T1 - Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study
AU - Jha, Vibhu
AU - Galati, Salvatore
AU - Volpi, Valerio
AU - Ciccone, Lidia
AU - Minutolo, Filippo
AU - Rizzolio, Flavio
AU - Granchi, Carlotta
AU - Poli, Giulio
AU - Tuccinardi, Tiziano
N1 - Publisher Copyright:
© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - ACLY
KW - consensus docking
KW - molecular dynamics
KW - pharmacophore
KW - virtual screening
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U2 - 10.1080/07391102.2020.1773314
DO - 10.1080/07391102.2020.1773314
M3 - Article
C2 - 32448086
AN - SCOPUS:85086784399
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
SN - 0739-1102
ER -