Comparison of 2DSimilarity and 3DSuperposition. Application to Searching a Conformational Drug Database

Abstract

In a database of about 2000 approved drugs, represented by 10(5) structural conformers, we have performed 2D comparisons (Tanimoto coefficients) and 3D superpositions. For one class of drugs the correlation between structural resemblance and similar action was analyzed in detail. In general Tanimoto coefficients and 3D scores give similar results, but we find that 2D similarity measures neglect important structural/funtional features. Examples for both over- and underestimation of similarity by 2D metrics are discussed. The required additional effort for 3D superpositions is assessed by implementation of a fast algorithm with a processing time below 0.01 s and a more sophisticated approach (0.5 s per superposition). According to the improvement of similarity detection compared to 2D screening and the pleasant rapidity on a desktop PC, full-atom 3D superposition will be an upcoming method of choice for library prioritization or similarity screening approaches.

CancerResource: a comprehensive database of cancer-relevant proteins and compound interactions supported by experimental knowledge

“…The biological activity of two compounds across the 60 NCI cell lines can be compared by a similarity measure, the Tanimoto coefficient of cellular fingerprints (30); this comparison by biological characteristics of a compound is a strong feature of the CancerResource web tool that complements the comparison of compounds by 2D structures. Here, the Tanimoto coefficient of structural fingerprints (35) enables the comparison of 2D similarities independently from the biological activity of a compound. CancerResource suggests thereby substitutability, alternative compound applications and support thereby drug research and drug treatment.…”

Superimpose: a 3D structural superposition server

“…This restriction of the search space allows to use an optimal branch-and-bound algorithm as described in ref. (8) without any reduction of the input molecules. To speed up the algorithm, also lower bounds for possible solutions along different paths in the search tree are calculated.…”

“…The algorithm was implemented to compare conformational databases of low molecular weight structures that share similar scaffold (8). …”

“…But a number of features of small molecules cannot be reflected adequately by 2D representations (6,7). Recent findings suggest that 3D similarity searches yield at least more varied results (8) than similarity comparisons via the usage of fingerprints or SMILES. Especially to find scaffold hoppers, 3D algorithms clearly show an advantage.…”

Using a pharmacophore representation concept to elucidate molecular similarity of dopamine antagonists

“…the 3D-superposition procedure available at the SuperDrug web server) [10]. Indeed, fast superposition algorithms tend to have certain limitations when applied to molecules with considerably different overall geometry [29].…”