title: Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change.
abstract: SLIDE software, which models the flexibility of protein and ligand side chains while docking, was used to screen several large databases to identify inhibitors of Brugia malayi asparaginyl-tRNA synthetase (AsnRS), a target for anti-parasitic drug design. Seven classes of compounds identified by SLIDE were confirmed as micromolar inhibitors of the enzyme. Analogs of one of these classes of inhibitors, the long side-chain variolins, cannot bind to the adenosyl pocket of the closed conformation of AsnRS due to steric clashes, though the short side-chain variolins identified by SLIDE apparently bind isosterically with adenosine. We hypothesized that an open conformation of the motif 2 loop also permits the long side-chain variolins to bind in the adenosine pocket and that their selectivity for Brugia relative to human AsnRS can be explained by differences in the sequence and conformation of this loop. Loop flexibility sampling using Rigidity Optimized Conformational Kinetics (ROCK) confirms this possibility, while scoring of the relative affinities of the different ligands by SLIDE correlates well with the compounds' ranks in inhibition assays. Combining ROCK and SLIDE provides a promising approach for exploiting conformational flexibility in structure-based screening and design of species selective inhibitors.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, East Lansing, MI 48824, USA.
authors.forename: Sai Chetan K
authors.initials: SC
authors.lastname: Sukuru
authors.forename: Thibaut
authors.initials: T
authors.lastname: Crepin
authors.forename: Youli
authors.initials: Y
authors.lastname: Milev
authors.forename: Liesl C
authors.initials: LC
authors.lastname: Marsh
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Hill
authors.forename: Regan J
authors.initials: RJ
authors.lastname: Anderson
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Morris
authors.forename: Anjali
authors.initials: A
authors.lastname: Rohatgi
authors.forename: Gavin
authors.initials: G
authors.lastname: O'Mahony
authors.forename: Morten
authors.initials: M
authors.lastname: Grøtli
authors.forename: Franck
authors.initials: F
authors.lastname: Danel
authors.forename: Malcolm G P
authors.initials: MG
authors.lastname: Page
authors.forename: Michael
authors.initials: M
authors.lastname: Härtlein
authors.forename: Stephen
authors.initials: S
authors.lastname: Cusack
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kron
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D001226:Aspartate-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017178:Brugia malayi / Q000201:enzymology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000145:classification; D005369:Filaricides / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D012346:RNA, Transfer, Amino Acyl / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D005369:Filaricides; D008024:Ligands; D012346:RNA, Transfer, Amino Acyl; D001226:Aspartate-tRNA Ligase; C029194:asparaginyl-tRNA synthetase