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A Distance Geometry Heuristic for Expanding the Range of Geometries Sampled During Conformational Search
 

Summary: A Distance Geometry Heuristic for Expanding the Range
of Geometries Sampled During Conformational Search
SERGEI IZRAILEV, FANGQIANG ZHU, DIMITRIS K. AGRAFIOTIS
Johnson & Johnson Pharmaceutical Research and Development, L.L.C, 665 Stockton Drive,
Exton, Pennsylvania 19341
Received 10 February 2006; Revised 19 April 2006; Accepted 24 April 2006
DOI 10.1002/jcc.20506
Published online 10 October 2006 in Wiley InterScience (www.interscience.wiley.com).
Abstract: A recent study of crystal structures of protein­ligand complexes has shown that bioactive conformations
tend to be more extended than random ones (Diller and Merz, J. Comput. Aid. Mol. Des. 2002, 16, 105­112). Exist-
ing conformational sampling techniques produce molecular conformations with a distribution of geometric sizes that
may not cover that of the bioactive conformations. Here, we describe a simple heuristic for biasing the conforma-
tional search toward more extended or compact conformations, while maintaining excellent sampling. The method
uses a boosting strategy to generate a series of conformations, each of which is at least as extended (or compact) as
the previous one. We demonstrate that this method significantly expands the range of geometric sizes generated dur-
ing the search and thus increases the efficiency of sampling bioactive conformations.
q 2006 Wiley Periodicals, Inc. J Comput Chem 27: 1962­1969, 2006
Key words: conformational analysis; bioactive conformation; stochastic proximity embedding; distance geometry;
boosting
Introduction

  

Source: Agrafiotis, Dimitris K. - Molecular Design and Informatics Group, Johnson & Johnson Pharmaceutical Research and Development

 

Collections: Chemistry; Computer Technologies and Information Sciences