title: Potential selective inhibitors against Rv0183 of Mycobacterium tuberculosis targeting host lipid metabolism.
abstract: Tuberculosis is the second leading infectious killer with 9 million new cases in 2009. Extensive use of pathogen's lipid metabolism especially in utilizing the host lipids and virulence highlights the importance of exported lipid-catabolizing enzymes. Current study aims to emphasize the importance of Rv0183, an exported monoacylglycerol lipase, involved in metabolizing the host cell membrane lipids. Sequence analysis and homology modeling shows Rv0183 is highly conserved throughout mycobacterial species even in Mycobacterium leprae and also significantly divergent from mammalian lipases. Additionally, employing virtual screening using NCI diversity set and ZINC database with criteria of molecules with higher predicted free energy of binding toward Rv0183 than human lipase, potential inhibitors have been identified for Rv0183. A tautomer of ZINC13451138, known inhibitor for HIV-1 integrase is the best hit with difference in free energy of binding of 8.72 kcal/mol. The sequence and structure analysis were helpful in identifying the ligand binding sites and molecular function of the mycobacterial specific monoacylglycerol lipase. Rv0183 represents a suitable and promising drug target and is also a step towards understanding dormancy development and reactivation, thereby addressing pathogen's drug resistance. Experimental studies on the discovered potential inhibitors in this virtual screen should further validate the therapeutic utility of Rv0183.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Saravanan
authors.forename: Vikash Kumar
authors.initials: VK
authors.lastname: Dubey
authors.forename: Sanjukta
authors.initials: S
authors.lastname: Patra
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology*; D016208:Databases, Factual; D006801:Humans; D006860:Hydrogen Bonding; D050356:Lipid Metabolism / Q000187:drug effects*; D056004:Molecular Dynamics Simulation; D008994:Monoacylglycerol Lipases / Q000737:chemistry / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D002264:Carboxylic Acids; D003510:Cyclohexanes; D010636:Phenols; C574249:ZINC13451138; D008994:Monoacylglycerol Lipases