Discovering new classes of Brugia malayi asparaginyl-tRNA synthetase inhibitors and relating specificity to conformational change.
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.
Sukuru
Sai Chetan K
SC
Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, East Lansing, MI 48824, USA.
Crepin
Thibaut
T
Milev
Youli
Y
Marsh
Liesl C
LC
Hill
Jonathan B
JB
Anderson
Regan J
RJ
Morris
Jonathan C
JC
Rohatgi
Anjali
A
O'Mahony
Gavin
G
Grøtli
Morten
M
Danel
Franck
F
Page
Malcolm G P
MG
Härtlein
Michael
M
Cusack
Stephen
S
Kron
Michael A
MA
Kuhn
Leslie A
LA
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*
D004791:Enzyme Inhibitors; D005369:Filaricides; D008024:Ligands; D012346:RNA, Transfer, Amino Acyl; D001226:Aspartate-tRNA Ligase; C029194:asparaginyl-tRNA synthetase