title: Structural analysis of trypanosomal sirtuin: an insight for selective drug design.
abstract: The infectious disease burden imposed by trypanosomatidae family continues to create burden in countries that are least equipped to bring new medicines to the clinic. For sickness caused by this family of parasites (African trypanosomiasis, Chagas disease, and leishmaniasis) no vaccines are available, and currently available drugs suffer from insufficient efficacy, excessive toxicity, and steady loss of effectiveness due to resistance. Availability of the genome sequence of pathogens of this family offers a unique avenue for the identification of novel common drug targets for all three pathogens. Sirtuin family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases are remarkably conserved throughout evolution from archaebacteria to eukaryotes and plays an important role in trypanosomatidae biology and virulence. In order to gain insight for selective drug design, three-dimensional (3D) models of L. major, L. infantum, T. brucie, and T. cruzi sirtuin were constructed by homology modeling and compared with human sirtuin. The molecular electrostatic potentials and cavity depth analysis of these models suggest that the inhibitor binding catalytic domain has various minor structural differences in the active site of trypanosomal and human sirtuin, regardless of sequence similarity. These studies have implications for designing effective strategies to identify inhibitors that can be developed as novel broad-spectrum antitrypanosomal drugs.
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S Nagar, Mohali, Punjab, 160062, India.
authors.forename: Simranjeet
authors.initials: S
authors.lastname: Kaur
authors.forename: Amol V
authors.initials: AV
authors.lastname: Shivange
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Roy
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D056564:Sirtuin 1 / Q000737:chemistry / Q000235:genetics; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D013045:Species Specificity; D055672:Static Electricity; D014351:Trypanosomatina / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics
chemical_list: C447939:SIRT1 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2