title: Molecular modeling and dynamics simulations of PNP from Streptococcus agalactiae.
abstract: This work describes for the first time a structural model of purine nucleoside phosphorylase from Streptococcus agalactiae (SaPNP). PNP catalyzes the cleavage of N-ribosidic bonds of the purine ribonucleosides and 2-deoxyribonucleosides in the presence of inorganic orthophosphate as a second substrate. This enzyme is a potential target for the development of antibacterial drugs. We modeled the complexes of SaPNP with 15 different ligands in order to determine the structural basis for the specificity of these ligands against SaPNP. The application of a novel empirical scoring function to estimate the affinity of a ligand for a protein was able to identify the ligands with high affinity for PNPs. The analysis of molecular dynamics trajectory for SaPNP indicates that the functionally important motifs have a very stable structure. This new structural model together with a novel empirical scoring function opens the possibility to explorer larger library of compounds in order to identify the new inhibitors for PNPs in virtual screening projects.
authors.affiliation: Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Av. Ipiranga, 6681, CEP 90619-900, Porto Alegre-RS, Brazil.
authors.forename: Rafael Andrade
authors.initials: RA
authors.lastname: Caceres
authors.forename: Luis Fernando
authors.initials: LF
authors.lastname: Saraiva Timmers
authors.forename: Raquel
authors.initials: R
authors.lastname: Dias
authors.forename: Luiz Augusto
authors.initials: LA
authors.lastname: Basso
authors.forename: Diogenes Santiago
authors.initials: DS
authors.lastname: Santos
authors.forename: Walter Filgueira
authors.initials: WF
authors.lastname: de Azevedo
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D003853:Deoxyribonucleosides / Q000737:chemistry; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D007288:Inosine / Q000031:analogs & derivatives / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011684:Purine Nucleosides / Q000737:chemistry; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016415:Sequence Alignment; D013292:Streptococcus agalactiae / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D003853:Deoxyribonucleosides; D008024:Ligands; D011684:Purine Nucleosides; C048246:5'-deoxy-5'-iodo-9-deazainosine; D006151:Guanosine; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase