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J Biomol Struct Dyn ; 32(4): 591-601, 2014 Apr.
Article in English | MEDLINE | ID: mdl-23663010

ABSTRACT

Enzymes involved in the pyrimidine biosynthesis pathway have become an important target for the pharmacological intervention. One among those enzymes, Aspartate Trans Carbamoylase (ATCase), catalyses the condensation of aspartate and carbamoyl phosphate to form N-carbamoyl-l-aspartate and inorganic phosphate. The present study provides the molecular insights into the enzyme ATCase. The three-dimensional structure of ATCase from Thermus thermophilus HB8 was modeled based on the crystal structure of ATCase in Pyrococcus abyssi (PDB ID:1ML4). Molecular dynamics simulation was performed to identify the conformational stability of TtATCase with and without its ligand complexes. Based on the pharmacokinetic properties and the glide-docking scores of ligands from four databases (Maybridge, Binding, Asinex and Technology for Organic Synthesis (TOS laboratory) for the screening of ligands, we identified four potential ligand molecules for TtATCase. From the molecular docking results, we proposed that the residues Thr53, Arg104, and Gln219 are consistently involved in strong hydrogen-bonding interactions and play a vital role in the TtATCase activity. From the results of molecular dynamics simulation, the ligand molecules are found to bind appropriately to the target enzyme. However, the structure of TtATCase needs to be determined experimentally to confirm this.


Subject(s)
Aspartate Carbamoyltransferase/chemistry , Models, Molecular , Thermus thermophilus/enzymology , Amino Acid Sequence , Aspartate Carbamoyltransferase/antagonists & inhibitors , Aspartate Carbamoyltransferase/metabolism , Binding Sites , Catalytic Domain , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , High-Throughput Screening Assays , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Sequence Data , Protein Binding , Protein Conformation , Pyrimidines/metabolism , Sequence Alignment , User-Computer Interface
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