02662nas a2200337   4500000000100000008004100001260001300042653002400055653002300079653001800102653002400120653002700144653001600171653002100187653002100208653002200229653002500251653002200276653002000298653002500318653003300343653002300376653003100399100001600430700001600446245019400462300001100656490000700667520163600674022001402310       2012                            d  c2012 Jan10aAmino Acid Sequence10aBacterial Proteins10aBinding Sites10aComputer Simulation10aCrystallography, X-Ray10aDrug Design10aEscherichia coli10aModels, Chemical10aModels, Molecular10aMycobacterium leprae10aPeptide Synthases10aProtein Binding10aProtein Conformation10aProtein Structure, Secondary10aSequence Alignment10aSequence Analysis, Protein1 aShanmugam A1 aNatarajan J00aComparative modeling of UDP-N-acetylmuramoyl-glycyl-D-glutamate-2, 6-diaminopimelate ligase from Mycobacterium leprae and analysis of its binding features through molecular docking studies.  a115-250 v183 a<p>Leprosy is an infectious disease caused by Mycobacterium leprae. The increasing drug and multi-drug resistance of M. leprae enforce the importance of finding new drug targets. Mycobacterium has unusually impermeable cell wall that contributes to considerable resistance to many drugs. Peptidoglycan is an important component of the cell wall of M. leprae. UDP-N-acetylmuramoyl-glycyl-D-glutamate-2, 6-diaminopimelate ligase (MurE) plays a crucial role in the peptidoglycan biosynthesis and hence it could be considered as a potential drug target for leprosy. Structure of this enzyme for M. leprae has not yet been elucidated. We modeled the three-dimensional structure of MurE from M. leprae using comparative modeling methods based on the X-ray crystal structure of MurE from E. coli and validated. The 3D-structure of M. leprae MurE enzyme was docked with its substrates meso-diaminopimelic acid (A2pm) and UDP-N-acetyl muramoyl-glycyl-D- glutamate (UMGG) and its product UDP-N-acetyl muramoyl-glycyl-D-glu-meso-A(2)pm (UTP) and also with ATP. The docked complexes reveal the amino acids responsible for binding the substrates. Superposition of these complex structures suggests that carboxylic acid group of UMGG is positioned in proximity to γ-phosphate of the ATP to facilitate the formation of acylphosphate intermediate. The orientation of an amino group of A(2)pm facilitates the nucleophilic attack to form the product. Overall, the proposed model together with its binding features gained from docking studies could help to design a truly selective ligand inhibitor specific to MurE for the treatment of leprosy.</p>  a0948-5023