02467nas a2200373   4500000000100000008004100001260001300042653002400055653002300079653001800102653002100120653002600141653002400167653001900191653003000210653002500240653001100265653002300276653001200299653003600311653002200347653002800369653003100397653002500428653002200453100001400475700001600489245012900505300001300634490000700647050001700654520140800671022001402079       2012                            d  c2012 Dec10aAmino Acid Sequence10aBacterial Proteins10aBinding Sites10aCluster Analysis10aComputational Biology10aComputer Simulation10aDrug Discovery10aDrug Resistance, Multiple10aEvolution, Molecular10aHumans10aLeprostatic Agents10aleprosy10aMetabolic Networks and Pathways10aModels, Molecular10aMolecular Sequence Data10aMutagenesis, Site-Directed10aMycobacterium leprae10aPeptide Synthases1 aAnusuya S1 aNatarajan J00aMulti-targeted therapy for leprosy: insilico strategy to overcome multi drug resistance and to improve therapeutic efficacy.  a1899-9100 v12  aANUSUYA 20123 a<p>Leprosy remains a major public health problem, since single and multi-drug resistance has been reported worldwide over the last two decades. In the present study, we report the novel multi-targeted therapy for leprosy to overcome multi drug resistance and to improve therapeutic efficacy. If multiple enzymes of an essential metabolic pathway of a bacterium were targeted, then the therapy would become more effective and can prevent the occurrence of drug resistance. The MurC, MurD, MurE and MurF enzymes of peptidoglycan biosynthetic pathway were selected for multi targeted therapy. The conserved or class specific active site residues important for function or stability were predicted using evolutionary trace analysis and site directed mutagenesis studies. Ten such residues which were present in at least any three of the four Mur enzymes (MurC, MurD, MurE and MurF) were identified. Among the ten residues G125, K126, T127 and G293 (numbered based on their position in MurC) were found to be conserved in all the four Mur enzymes of the entire bacterial kingdom. In addition K143, T144, T166, G168, H234 and Y329 (numbered based on their position in MurE) were significant in binding substrates and/co-factors needed for the functional events in any three of the Mur enzymes. These are the probable residues for designing newer anti-leprosy drugs in an attempt to reduce drug resistance.</p>  a1567-7257