Bioisosterism as a Molecular Diversity Descriptor:  Steric Fields of Single “Topomeric” Conformers

Abstract

The comparative molecular field analysis steric field of a single “topomeric” conformer is introduced as a molecular diversity descriptor particularly useful for combinatorial chemistry involving variations around a fixed “core”. Using this new descriptor, 736 commercially available thiols are divided into 231 bioisosteric clusters, whose compositions agree at least as well with medicinal chemical experience and intuition as do clusters derived from Tanimoto differences between 2D fragment occurrences. However, in practice topomeric steric fields complement 2D fingerprints, being the two most frequently useful descriptors yet found for neighborhood-based design of combinatorial libraries.

A comparison of ligand based virtual screening methods and application to corticotropin releasing factor 1 receptor

“…The steric fields are generated in a similar way to CoMFA using an sp 3 carbon atom probe on a 2 Å lattice surrounding the fragment. The steric field differs from the CoMFA equivalent as the atomic contribution diminishes with distance from the valence bond, being scaled according to the formula 0.85 n where n is essentially the number of intervening double bonds [46]. The absence of pharmacophoric features in 3D space yields a penalty to the similarity between two fragments.…”

Balancing Representativeness Against Diversity using Optimizable K-Dissimilarity and Hierarchical Clustering

“…Indeed, hierarchical clustering based on molecular fields 3 or on 2D structural fingerprints 4 have both been shown to give intuitively satisfactory results; moreover, some clustering methods seem to give quantitatively better results than do others. 5,6 One thrust of this report is to explore how the hierarchical clustering method used affects the trade-off between representativeness and diversity.…”

AllChem: generating and searching 1020 synthetically accessible structures

“…The principles of topomer shape similar [31] or shape superior (3D-QSAR based) searching [32] have been described elsewhere. However, one important question, especially with so many structures, is validation of the search process.…”