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Conformational Sampling of Bioactive Molecules: A Comparative Study Dimitris K. Agrafiotis,* Alan C. Gibbs, Fangqiang Zhu, Sergei Izrailev,, and Eric Martin
 

Summary: Conformational Sampling of Bioactive Molecules: A Comparative Study
Dimitris K. Agrafiotis,* Alan C. Gibbs, Fangqiang Zhu, Sergei Izrailev,, and Eric Martin
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 665 Stockton Drive, Exton,
Pennsylvania 19341, and Novartis, 4560 Horton Street, Emeryville, California 94608
Received December 4, 2006
The necessity to generate conformations that sample the entire conformational space accessible to a given
molecule is ubiquitous in the field of computer-aided drug design. Protein-ligand docking, 3D database
searching, and 3D QSAR are three commonly used techniques that depend critically upon the quality and
diversity of the generated conformers. Although there are a wide range of conformational search algorithms
available, the extent to which they sample conformational space is often unclear. To address this question,
we conducted a robust comparison of the search algorithms implemented in several widely used molecular
modeling packages, including Catalyst, Macromodel, Omega, MOE, and Rubicon as well as our own method,
stochastic proximity embedding (SPE). We found that SPE used in conjunction with conformational boosting,
a heuristic for biasing conformational search toward more extended or compact geometries, along with
Catalyst, are significantly more effective in sampling the full range of conformational space compared to
the other methods, which show distinct preferences for either more extended or more compact geometries.
INTRODUCTION
Most organic molecules of nontrivial size are not just three-
dimensional, they are "four-dimensional", because they exist
as an ensemble of three-dimensional conformations inter-

  

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

 

Collections: Chemistry; Computer Technologies and Information Sciences