Molecular modeling and dynamics simulations of PNP from Streptococcus agalactiae.
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.
Caceres
Rafael Andrade
RA
Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Av. Ipiranga, 6681, CEP 90619-900, Porto Alegre-RS, Brazil.
Saraiva Timmers
Luis Fernando
LF
Dias
Raquel
R
Basso
Luiz Augusto
LA
Santos
Diogenes Santiago
DS
de Azevedo
Walter Filgueira
WF
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
D003853:Deoxyribonucleosides; D008024:Ligands; D011684:Purine Nucleosides; C048246:5'-deoxy-5'-iodo-9-deazainosine; D006151:Guanosine; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase