title: Structure-guided fragment-based in silico drug design of dengue protease inhibitors.
abstract: An in silico fragment-based drug design approach was devised and applied towards the identification of small molecule inhibitors of the dengue virus (DENV) NS2B-NS3 protease. Currently, no DENV protease co-crystal structure with bound inhibitor and fully formed substrate binding site is available. Therefore a homology model of DENV NS2B-NS3 protease was generated employing a multiple template spatial restraints method and used for structure-based design. A library of molecular fragments was derived from the ZINC screening database with help of the retrosynthetic combinatorial analysis procedure (RECAP). 150,000 molecular fragments were docked to the DENV protease homology model and the docking poses were rescored using a target-specific scoring function. High scoring fragments were assembled to small molecule candidates by an implicit linking cascade. The cascade included substructure searching and structural filters focusing on interactions with the S1 and S2 pockets of the protease. The chemical space adjacent to the promising candidates was further explored by neighborhood searching. A total of 23 compounds were tested experimentally and two compounds were discovered to inhibit dengue protease (IC(50) = 7.7 μM and 37.9 μM, respectively) and the related West Nile virus protease (IC(50) = 6.3 μM and 39.0 μM, respectively). This study demonstrates the successful application of a structure-guided fragment-based in silico drug design approach for dengue protease inhibitors providing straightforward hit generation using a combination of homology modeling, fragment docking, chemical similarity and structural filters.
authors.affiliation: Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance and Frankfurt Institute for Advanced Studies, J.W. Goethe-University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Knehans
authors.forename: Andreas
authors.initials: A
authors.lastname: Schüller
authors.forename: Danny N
authors.initials: DN
authors.lastname: Doan
authors.forename: Kassoum
authors.initials: K
authors.lastname: Nacro
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.forename: Peter
authors.initials: P
authors.lastname: Güntert
authors.forename: M S
authors.initials: MS
authors.lastname: Madhusudhan
authors.forename: Tanja
authors.initials: T
authors.lastname: Weil
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D003715:Dengue / Q000188:drug therapy; D003716:Dengue Virus / Q000201:enzymology*; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D014902:West Nile virus / Q000201:enzymology; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D010450:Endopeptidases; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases