High-throughput docking for the identification of new influenza A virus polymerase inhibitors targeting the PA-PB1 protein-protein interaction

Cristina Tintori; Ilaria Laurenzana; Anna Lucia Fallacara; Ulrich Kessler; Beatrice Pilger; Lilli Stergiou; Maurizio Botta

doi:10.1016/j.bmcl.2013.11.019

High-throughput docking for the identification of new influenza A virus polymerase inhibitors targeting the PA-PB1 protein-protein interaction

Bioorg Med Chem Lett. 2014 Jan 1;24(1):280-2. doi: 10.1016/j.bmcl.2013.11.019. Epub 2013 Nov 21.

Authors

Cristina Tintori¹, Ilaria Laurenzana², Anna Lucia Fallacara³, Ulrich Kessler⁴, Beatrice Pilger⁴, Lilli Stergiou⁴, Maurizio Botta⁵

Affiliations

¹ Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro, 53100 Siena, Italy.
² IRCCS-Centro di Riferimento Oncologico Basilicata (CROB), Laboratory of Preclinical and Translational Research, Via Padre Pio 1, Rionero in Vulture, 85028 Potenza, Italy.
³ Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro, 53100 Siena, Italy; Dipartimento di Chimica e Tecnologie del Farmaco, Università La Sapienza, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
⁴ PiKe Pharma GmbH, Institute of Pharmaceutical Sciences, Swiss Federal Institute for Technology, CH-8093 Zürich, Switzerland.
⁵ Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, via A. Moro, 53100 Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA. Electronic address: botta.maurizio@gmail.com.

PMID: 24314669
DOI: 10.1016/j.bmcl.2013.11.019

Abstract

A high-throughput molecular docking approach was successfully applied for the selection of potential inhibitors of the Influenza RNA-polymerase which act by targeting the PA-PB1 protein-protein interaction. Commercially available compounds were purchased and biologically evaluated in vitro using an ELISA-based assay. As a result, some compounds possessing a 3-cyano-4,6-diphenyl-pyridine nucleus emerged as effective inhibitors with the best ones showing IC50 values in the micromolar range.

Keywords: Antiviral agents; High-throughput docking; Influenza virus; PA–PB1 interaction; Viral RNA polymerase; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
High-Throughput Screening Assays
Influenza A virus / enzymology*
Models, Molecular
Molecular Structure
Protein Binding / drug effects
Pyridines / chemistry
Pyridines / pharmacology*
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
RNA-Dependent RNA Polymerase / metabolism
Structure-Activity Relationship
Viral Proteins / antagonists & inhibitors*
Viral Proteins / metabolism

Substances

Enzyme Inhibitors
PA protein, influenza viruses
PB2 protein, influenza virus
Pyridines
Viral Proteins
RNA-Dependent RNA Polymerase