title: Homology Model-Based Virtual Screening for the Identification of Human Helicase DDX3 Inhibitors.
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.
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. De Gasperi 2, I-53100 Siena, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fazi
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. De Gasperi 2, I-53100 Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. De Gasperi 2, I-53100 Siena, Italy.
authors.forename: Annalaura
authors.initials: A
authors.lastname: Brai
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. De Gasperi 2, I-53100 Siena, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Botta
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. De Gasperi 2, I-53100 Siena, Italy.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Selvaraj
authors.affiliation: Istituto di Genetica Molecolare, IGM-CNR , Via Abbiategrasso 207, I-27100 Pavia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Garbelli
authors.affiliation: Istituto di Genetica Molecolare, IGM-CNR , Via Abbiategrasso 207, I-27100 Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via A. De Gasperi 2, I-53100 Siena, Italy.|Biotechnology College of Science and Technology, Temple University , Biolife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, United States.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D012367:RNA, Viral / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D012367:RNA, Viral; D054852:Small Molecule Libraries; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases