Sampling conformational hyperspace: Techniques for improving completeness

Abstract

Three new strategies for sampling the conformation space accessible to a series of structurally diverse, flexible molecules are defined and compared to samples obtained using a fixed-grid torsion angle sampling strategy. A set of 28 potent inhibitors of angiotensin converting enzyme selected by Mayer et al. [J. Comput.-Aided Mol. Design, 1 (1987) 3] and the unrestricted active-site model proposed by Waller et al. [to be published] are used to produce a realistic experimental setting. We modified our Constrained Search algorithm [Dammkoehler et al., J. Comput.-Aided Mol. Design, 3 (1989) 3] to support these new sampling strategies, performing a series of 64 simulations (search experiments) and generating a large set of sterically allowed conformations. In each experiment, we systematically vary the internal torsion angles in each molecule using one of the sampling strategies. The common orientations of preselected functional groups thought to represent those dominating the interaction with the enzyme and presented by the set of molecules are classified and recorded for each experiment. Pairwise distances between groups are used to characterize the geometry of the common orientations. The results of each experiment, represented by a set of distance values, are compared and combined to evaluate the completeness of the conformational sampling. While no pure strategy or single search experiment was found to be adequate to fully explore the set of common sterically allowed conformations, a new sampling technique, called adaptive radial sampling, is shown to be significantly more complete than the commonly used fixed grid sampling.

History and Evolution of the Pharmacophore Concept in Computer-Aided Drug Design

“…A celebrated example is the application of this approach to angiotensin-converting enzyme (ACE) inhibitors by Mayer and co-workers [46], and later by Dammkoehler and co-workers [47]. In cases where the receptor enzyme information is not available, conformation driven pharmacophores still provide valuable opportunity to identify potential active compounds (ligand based design).…”

Conformational Sampling and Energetics of Drug-Like Molecules

“…In such scheme, the torsions are sampled with a pre-defined granularity (e.g., every 60 degrees [165]), thus it is called a grid search, or systematic search, to stress the intention to sample the conformational space uniformly via all discrete torsional combinations [126,165,[181][182][183][184]. Such search strategy can be represented as a tree [51,182] with a root node and branches to deeper nodes organized in successive levels (Fig.…”

Conformational and Energetic Aspects of Receptor—Ligand Recognition

“…The construction of pharmacophore models (a pharmacophore is a spatial arrangement of atoms that may give rise to a biological activity) is a key process in computer assisted drug design (28)(29)(30). In pharmacophore mapping techniques (2,(31)(32)(33) the assumptions are often made that (i) there exists a commonality between isolated structures of ligands (2) and (ii) their low energy solution structures are similar to the conformations they adopt in the receptor binding site. The importance of this similarity extends beyond the scope of computer assisted drug design to questions related to the physics of binding.…”

“…The resulting 100 structures were miriimized by 1000 steps conjugent gradient and subsequently clustered by a hierarchical agglomerative method (36) based on the torsion angle metric and the anchor point distance metric. Representative structures from solution were generated by a systematic search (33), sampling important rotatable bonds in 15° increments. The resulting structures were minimized using 1000 steps of conjugent gradient minimization and then clustered based on the two metrics.…”