caa a22 4500 467938857 CHVBK 20180406153006.0 cr unu---uuuuu 170328e20060301xx s 000 0 eng 10.1007/s10822-006-9043-5 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9043-5 Discovering New Classes of Brugiamalayi Asparaginyl-tRNA Synthetase Inhibitors and Relating Specificity to Conformational Change [Elektronische Daten] [Sai Sukuru, Thibaut Crepin, Youli Milev, Liesl Marsh, Jonathan Hill, Regan Anderson, Jonathan Morris, Anjali Rohatgi, Gavin O'Mahony, Morten Grøtli, Franck Danel, Malcolm Page, Michael Härtlein, Stephen Cusack, Michael Kron, Leslie Kuhn] 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 Brugiamalayi 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. Springer Science+Business Media, Inc., 2006 Conformational flexibility nationallicence Docking nationallicence Inhibitor design nationallicence Sampling nationallicence Scoring nationallicence Screening nationallicence Anti-parasitic agents nationallicence MSU ProFlex nationallicence ROCK nationallicence SLIDE nationallicence AARS : aminoacyl-tRNA synthetases nationallicence ASNAMS : asparaginyl sulfamoyl adenylate nationallicence AsnRS : asparaginyl-tRNA synthetase nationallicence CSD : Cambridge Structural Database nationallicence LBHAMP : l-aspartate-β-hydroxamate adenylate nationallicence MD : molecular dynamics nationallicence PDB : Protein Data Bank nationallicence SMEVAR : S-methyl-deoxyvariolin B nationallicence Sukuru Sai Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, 48824, East Lansing, MI, USA aut Crepin Thibaut European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France aut Milev Youli Department of Medicine and Institute of International Health, Michigan State University, East Lansing, MI, USA aut Marsh Liesl Department of Chemistry, University of Canterbury, Christchurch, New Zealand aut Hill Jonathan Department of Chemistry, University of Canterbury, Christchurch, New Zealand aut Anderson Regan Department of Chemistry, University of Canterbury, Christchurch, New Zealand aut Morris Jonathan School of Chemistry and Physics, The University of Adelaide, Adelaide, Australia aut Rohatgi Anjali Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, 48824, East Lansing, MI, USA aut O'Mahony Gavin Department of Chemistry, Göteborg University, Göteborg, Sweden aut Grøtli Morten Department of Chemistry, Göteborg University, Göteborg, Sweden aut Danel Franck Basilea Pharmaceutica Limited, Basel, Switzerland aut Page Malcolm Basilea Pharmaceutica Limited, Basel, Switzerland aut Härtlein Michael Large Scale Structures Group, Institute Laue-Langevin, Grenoble, France aut Cusack Stephen European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France aut Kron Michael Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, 48824, East Lansing, MI, USA aut Kuhn Leslie Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, 48824, East Lansing, MI, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/3(2006-03-01), 159-178 0920-654X 20:3<159 2006 20 10822 https://doi.org/10.1007/s10822-006-9043-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9043-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sukuru Sai Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, 48824, East Lansing, MI, USA aut NATIONALLICENCE 700 1- Crepin Thibaut European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France aut NATIONALLICENCE 700 1- Milev Youli Department of Medicine and Institute of International Health, Michigan State University, East Lansing, MI, USA aut NATIONALLICENCE 700 1- Marsh Liesl Department of Chemistry, University of Canterbury, Christchurch, New Zealand aut NATIONALLICENCE 700 1- Hill Jonathan Department of Chemistry, University of Canterbury, Christchurch, New Zealand aut NATIONALLICENCE 700 1- Anderson Regan Department of Chemistry, University of Canterbury, Christchurch, New Zealand aut NATIONALLICENCE 700 1- Morris Jonathan School of Chemistry and Physics, The University of Adelaide, Adelaide, Australia aut NATIONALLICENCE 700 1- Rohatgi Anjali Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, 48824, East Lansing, MI, USA aut NATIONALLICENCE 700 1- O'Mahony Gavin Department of Chemistry, Göteborg University, Göteborg, Sweden aut NATIONALLICENCE 700 1- Grøtli Morten Department of Chemistry, Göteborg University, Göteborg, Sweden aut NATIONALLICENCE 700 1- Danel Franck Basilea Pharmaceutica Limited, Basel, Switzerland aut NATIONALLICENCE 700 1- Page Malcolm Basilea Pharmaceutica Limited, Basel, Switzerland aut NATIONALLICENCE 700 1- Härtlein Michael Large Scale Structures Group, Institute Laue-Langevin, Grenoble, France aut NATIONALLICENCE 700 1- Cusack Stephen European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France aut NATIONALLICENCE 700 1- Kron Michael Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, 48824, East Lansing, MI, USA aut NATIONALLICENCE 700 1- Kuhn Leslie Department of Biochemistry and Molecular Biology, Michigan State University, 502C Biochemistry Building, 48824, East Lansing, MI, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/3(2006-03-01), 159-178 0920-654X 20:3<159 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer