Normal mode-based approaches in receptor ensemble docking

CAVASOTTO, CLAUDIO N.

METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.)

SPRINGER

Año: 2012 vol. 819 p. 157 - 168

1064-3745

Explicitly accounting for target flexibility in docking still constitutes a difficult challenge due to the high dimensionality of the conformational space to be sampled.  This especially applies to the high-throughput scenario, where the screening of hundreds of thousands compounds takes place.  The use of multiple receptor conformations to perform ensemble docking in a sequential fashion is a simple but powerful approach that allows to incorporate binding site structural diversity in the docking process.  Whenever enough experimental structures to build a diverse ensemble are not available, normal mode analysis provides an appealing and efficient approach to in silico generate multiple receptor conformations by distortion along few low-frequency modes that represent collective mid- and large-scale displacements.  In this way, the dimension of the conformational space to be sampled is heavily reduced.  This methodology is especially suited to incorporate target flexibility at the backbone level.  In this Chapter, the main components of normal mode-based approaches in the context of ensemble docking are presented and explained, including the theoretical and  practical considerations needed for the successful development and implementation of this methodology.