Technique for generating three-dimensional alignments of multiple ligands from one-dimensional alignments

Journal of Chemical Information and Modeling
Andrei V AnghelescuDavid J Diller

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.

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Citations

Apr 28, 2012·Journal of Computer-aided Molecular Design·Robin TaylorOliver Korb
Jul 17, 2012·Journal of Chemical Information and Modeling·Thomas KlabundeAndreas Evers
Mar 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Graeme O'BoyleJohn A Kirby
Nov 20, 2014·Journal of Computer-aided Molecular Design·Daniel CappelJianxin Duan
Jul 12, 2010·Molecular Informatics·Thierry Langer
Jul 5, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Graeme O'BoyleJohn A Kirby
Oct 17, 2009·Journal of Medicinal Chemistry·Andrew R LeachRobin Taylor

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