Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/6541
Title: Homology Model-Based Virtual Screening for the Identification of Human Helicase DDX3 Inhibitors
Authors: FAZI, ROBERTA
TINTORI, CRISTINA
BRAI, ANNALAURA
Botta, Lorenzo
Selvaraj, Manikandan
Garbelli, Anna
Maga, Giovanni
Botta, Maurizio 
Issue Date: 2015
Project: None 
Journal: JOURNAL OF CHEMICAL INFORMATION AND MODELING
Abstract: 
Targeting cellular cofactors instead of viral enzymes represents a new strategy to combat infectious diseases, which should help to overcome the problem of viral resistance. Recently, it has been revealed that the cellular ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3) is an essential host factor for the replication of several viruses such as HIV, HCV, JEV, Dengue, and West Nile. Accordingly, a drug targeting DDX3 could theoretically inhibit all viruses that are dependent on this host factor. Herein, for the first time, a model of hDDX3 in its closed conformation, which binds the viral RNA was developed by using the homology module of Prime through the Maestro interface of Schrodinger. Next, a structure-based virtual screening protocol was applied to identify DDX3 small molecule inhibitors targeting the RNA binding pocket. As a result, an impressive hit rate of 40% was obtained with the identification of 10 active compounds out of the 25 tested small molecules. The best poses of the active ligands highlighted the crucial residues to be targeted for the inhibition of the helicase activity of DDX3. The obtained results confirm the reliability of the constructed DDX3/RNA model and the proposed computational strategy for investigating novel DDX3 inhibitors.
Description: 
204463
URI: http://hdl.handle.net/20.500.12779/6541
ISSN: 1549-9596
DOI: 10.1021/acs.jcim.5b00419
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