title: Resisting resistant Mycobacterium tuberculosis naturally: mechanistic insights into the inhibition of the parasite's sole signal peptidase Leader peptidase B.
abstract: Tuberculosis (TB) is the second highest cause of mortality after HIV/AIDS and is one of the leading public health problems worldwide. The growing resistance to anti-TB drugs and the recalcitrant nature of tenacious infections present arduous challenges for the treatment of TB. Thus, the need to develop therapeutics against novel drug targets to help overcome multi-drug resistant TB is inevitable. Leader peptidase B (LepB), the sole signal peptidase of Mycobacterium tuberculosis (MTb), is one such potential drug target. The present work aims at identifying potential inhibitors of LepB, so as to repress the formation of the functional proteins essential for the growth and pathogenesis of MTb. In this study, we screened a large dataset of natural compounds against LepB using a high throughput approach. The screening was directed toward a binding pocket consisting of residues, some of which are critical for the catalytic activity of the enzyme, while others are part of the conserved domains of the signal peptidases. We also carried out molecular dynamics simulations of the two top-scoring compounds in order to study their molecular interactions with the active site functional residues of LepB and also to assess their dynamic behavior. We report herein two prospective non-covalent type inhibitory drugs of natural origin which are active against tuberculosis. These lead molecules possess improved binding properties, have low toxicity and are specific against MTb.
authors.affiliation: Department of Biotechnology, Delhi Technological University, New Delhi 110042, India.
authors.forename: Heena
authors.initials: H
authors.lastname: Dhiman
authors.forename: Jaspreet Kaur
authors.initials: JK
authors.lastname: Dhanjal
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Sharma
authors.forename: Sajeev
authors.initials: S
authors.lastname: Chacko
authors.forename: Sonam
authors.initials: S
authors.lastname: Grover
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry; D002109:Caffeic Acids / Q000494:pharmacology; D020134:Catalytic Domain; D002867:Chromones / Q000494:pharmacology; D062313:Databases, Pharmaceutical; D004187:Disaccharides / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D004789:Enzyme Activation; D057166:High-Throughput Screening Assays; D008024:Ligands; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001688:Biological Products; D002109:Caffeic Acids; D002867:Chromones; D004187:Disaccharides; D008024:Ligands; D008565:Membrane Proteins; D012697:Serine Endopeptidases; C026515:type I signal peptidase