Top ranked fragments from the virtual screen mimic portions of known inhibitors of p38 MAP kinase.

2010-04-09T01:21:06Z (GMT) by Niu Huang Matthew P. Jacobson
<p>(A) The high affinity inhibitor BIRB796 (stick) is shown bound to p38 MAP kinase (1kv2). Key hydrogen bonding interactions—between the morpholino group and the main chain amide of residue Met109, the urea group and the side chain carboxylate group of conserved residue Glu71, and the main chain amide of residue Asp168—are illustrated with yellow lines. Portions of the ligand are colored for comparison with fragments in panels (C) and (D). (B) A low-affinity ligand BMU (stick) is shown bound to the allosteric pocket (1kv1). (C) Three partially overlapping top fragment hits (stick) identified from virtual screening against the 1kv2 structure are shown: a pyridinyl-imidazole type of fragment (carbon atoms colored green, rank 155 in the virtual screen) bound to the ATP binding pocket; a urea-like moiety on a substituted naphthyl ring (carbon atoms colored cyan, rank 55) interacting with the Glu71 sidechain and the lipophilic pocket; and a substituted heterocyclic ring (carbon atoms colored magenta, rank 165) deeply buried into the allosteric binding pocket. (D) The overlap of three top scored fragment hits identified from virtual screening against the 1kv1 structure (ranks 6, 136 and 210). Molecular images were generated with UCSF Chimera <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010109#pone.0010109-Pettersen1" target="_blank">[42]</a>.</p>