title: Three dimensional model of severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain and molecular design of severe acute respiratory syndrome coronavirus helicase inhibitors.
abstract: The modeling of the severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain was performed using the protein structure prediction Meta Server and the 3D Jury method for model selection, which resulted in the identification of 1JPR, 1UAA and 1W36 PDB structures as suitable templates for creating a full atom 3D model. This model was further utilized to design small molecules that are expected to block an ATPase catalytic pocket thus inhibit the enzymatic activity. Binding sites for various functional groups were identified in a series of molecular dynamics calculation. Their positions in the catalytic pocket were used as constraints in the Cambridge structural database search for molecules having the pharmacophores that interacted most strongly with the enzyme in a desired position. The subsequent MD simulations followed by calculations of binding energies of the designed molecules were compared to ATP identifying the most successful candidates, for likely inhibitors - molecules possessing two phosphonic acid moieties at distal ends of the molecule.
authors.affiliation: BioInfoBank Institute, ul. Limanowskiego 24A, 60-744 Poznan, Poland. mmh@bioinfo.pl
authors.forename: Marcin
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Krystian
authors.initials: K
authors.lastname: Eitner
authors.forename: Marcin
authors.initials: M
authors.lastname: von Grotthuss
authors.forename: Leszek
authors.initials: L
authors.lastname: Rychlewski
authors.forename: Ewa
authors.initials: E
authors.lastname: Banachowicz
authors.forename: Tomasz
authors.initials: T
authors.lastname: Grabarkiewicz
authors.forename: Tomasz
authors.initials: T
authors.lastname: Szkoda
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kolinski
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D017124:Conserved Sequence; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D004265:DNA Helicases