title: Investigation of vital pathogenic target orotate phosphoribosyltransferases (OPRTase) from Thermus thermophilus HB8: Phylogenetic and molecular modeling approach.
abstract: Biosynthesis pathways of pyrimidine and purine are shown to play an important role in regular cellular activities. The biosynthesis can occur either through de novo or salvage pathways based on the requirement of the cell. The pyrimidine biosynthesis pathway has been linked to several disorders and various autoimmune diseases. Orotate phosphoribosyl transferase (OPRTase) is an important enzyme which catalyzes the conversion of orotate to orotate monophosphate in the fifth step of pyrimidine biosynthesis. Phylogenetic analysis of 228 OPRTase sequences shows the distribution of proteins across different living forms of life. High structural similarities between Thermusthermophilus and other organisms kindled us to concentrate on OPRTase as an anti-pathogenic target. In this study, a homology model of OPRTase was constructed using 2P1Z as a template. About 100 ns molecular dynamics simulation was performed to investigate the conformational stability and dynamic patterns of the protein. The amino acid residues (Met1, Asp2, Glu43, Ala44, Glu47, Lys51, Ala157 and Leu158) lining in the binding site were predicted using SiteMap. Further, structure based virtual screening was performed on the predicted binding site using ChemBridge, Asinex, Binding, NCI, TosLab and Zinc databases. Compounds retrieved from the screening collections were manually clustered. The resultant protein-ligand complexes were subjected to molecular dynamics simulations, which further validates the binding modes of the hits. The study may provide better insight for designing potent anti-pathogenic agent.
authors: Room No. 402, Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Science Campus, Karaikudi 630004, India.
authors: Kanagarajan
authors: K
authors: Surekha
authors: Room No. 402, Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Science Campus, Karaikudi 630004, India.
authors: Damodharan
authors: D
authors: Prabhu
authors: Room No. 402, Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Science Campus, Karaikudi 630004, India.
authors: Mariadasse
authors: M
authors: Richard
authors: Room No. 402, Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Science Campus, Karaikudi 630004, India.
authors: Mutharasappan
authors: M
authors: Nachiappan
authors: Room No. 402, Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Science Campus, Karaikudi 630004, India.
authors: Jayashree
authors: J
authors: Biswal
authors: Room No. 402, Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Science Campus, Karaikudi 630004, India. Electronic address: jjbioinformatics@gmail.com.
authors: Jeyaraman
authors: J
authors: Jeyakanthan
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009962:Orotate Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D009963:Orotic Acid / Q000737:chemistry* / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D016963:Thermus thermophilus / Q000737:chemistry / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D009963:Orotic Acid; D009962:Orotate Phosphoribosyltransferase
keywords: De novo pathway; Molecular dynamic simulation; Structure based virtual screening; TTHA1742