Unconventional 2D Shape Similarity Method Affords Comparable Enrichment as a 3D Shape Method in Virtual Screening Experiments

Abstract

3D molecular shape similarity search has recently become an attractive method for virtual screening and scaffold hopping in drug discovery and chemical genomics research. Among these 3D similarity methods is ROCS (Rapid Overlay of Chemical Structures), a popular tool because of its efficiency and effectiveness. However, searching a large multiconformer molecular database remains a very challenging task because of the nature of such calculations. To simplify shape similarity calculations and potentially increase the efficiency for large scale virtual screening, we have explored an alternative shape similarity approach that does not depend on multiconformers of molecules. The hypothesis underlying this approach is that similar chemical structures tend to have similar 2D chemical depictions and that shape comparison techniques can be utilized to effectively compare the shapes between chemical depictions. We use a 2D depiction program to generate 2-D chemical drawings for both the query molecule and database molecules. We have built a 2D shape comparison program based on the OESHAPE Toolkit (OE Scientific, NM) that compares the molecular depictions and quantifies the shape similarity between the molecules. We demonstrate that this unconventional 2D shape similarity method performs fairly well in virtual screening experiments compared to the 3D Shape method ROCS, with an added advantage of its computational efficiency.

Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints

“…It should be noted that most molecules in DUD and ZINC are rod-like or at best 2-dimensional with only very few 3D-shaped molecules (Figure 4 E/F). The very low shape diversity in these databases might partly contribute to the similar LBVS performance of 3D and 2D methods with DUD also noted in previous literature reports [ 18 , 33 , 41 , 42 , 46 - 49 ].…”

Shape‐based similarity searching in chemical databases

“…As an illustration that the distinction between these methods is not clear‐cut, a novel modification of the Gaussian overlay approach has recently been described (EZSim), which applies the Gaussian shape similarity method to a 2D representation of the molecule. Thus this is a 3D method applied to 2D representations 82. Performance, as measured by ROCS AUC values obtained from DUD database searches, is similar to those achieved with ROCS at a much reduced computational cost.…”

How to Valorize Biodiversity? Letʼs Go Hashing, Extracting, Filtering, Mining, Fishing

“…This, in any case, raises the question if such a conformation is biologically significant [88]. The performance of 2D and 3D similarity approaches has been compared directly in a number of applications, including virtual screening [89][90][91][92]. Since 3D similarity searching should incorporate, at least in principle, more accurate features than 2D methods, it would be expected that the results obtained from 3D methods should be more reliable than those obtained by 2D methods.…”