Technique for Generating Three-Dimensional Alignments of Multiple Ligands from One-Dimensional Alignments

Abstract

We describe and demonstrate a method for the simultaneous, fully flexible alignment of multiple molecules with a common biological activity. The key aspect of the algorithm is that the alignment problem is first solved in a lower dimensional space, in this case using the one-dimensional representations of the molecules. The three-dimensional alignment is then guided by constraints derived from the one-dimensional alignment. We demonstrate using 10 hERG channel blockers, with a total of 72 rotatable bonds, that the one-dimensional alignment is able to effectively isolate key conserved pharmacophoric features and that these conserved features can effectively guide the three-dimensional alignment. Further using 10 estrogen receptor agonists and 5 estrogen receptor antagonists with publicly available cocrystal structures we show that the method is able to produce superpositions comparable to those derived from crystal structures. Finally, we demonstrate, using examples from peptidic CXCR3 agonists, that the method is able to generate reasonable binding hypotheses.

Chemokine receptor CXCR3 agonist prevents human T-cell migration in a humanized model of arthritic inflammation

“…Discussion PS372424 is a small-molecule agonist for CXCR3 that was identified during a screen for antagonist compounds (19). The agonist has a peptidic structure containing a tetrahydroisoquinoline-arginine motif that closely aligns with a Pro-Arg motif at residues 35-39 of CXCL10; this motif is important for CXCR3 activation (22). PS372424 activated ERK in T cells with a similar potency and kinetic to the natural ligand CXCL11.…”

Small molecule chemokine mimetics suggest a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3

“…This was carried out using a novel multiple ligand alignment method as previously described (Anghelescu et al ., 2008). Visualization of the CXCL10 crystal structure (Booth et al ., 2002) was carried out using PyMol (DeLano, 2002), using structure 1LV9 from the Protein Data Bank (http://www.rcsb.org/pdb/home/home.do).…”

Pharmacophore Models for Virtual Screening

“…In addition, many other pharmacophore elucidation algorithms have been described, especially in the last few years [34][35][36][37][38][39][40][41][42], probably as a reaction to the more and more disappointing performance of docking-and scoringbased VS approaches.…”