Homology Model-Based Virtual Screening for the Identification of Human Helicase DDX3 Inhibitors

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• 作者：Roberta Fazi ; Cristina Tintori ; Annalaura Brai ; Lorenzo Botta ; Manikandan Selvaraj ; Anna Garbelli ; Giovanni Maga ; Maurizio Botta
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2015
• 出版时间：November 23, 2015
• 年：2015
• 卷：55
• 期：11
• 页码：2443-2454
• 全文大小：868K
• ISSN：1549-960X

文摘

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.