New method for rapid characterization of molecular shapes: applications in drug design

Abstract

We present a method for the rapid quantitative shape match between two molecules or a molecule and a template, using atom triplets as descriptors. This technique can be used either as a rapid screen preceding the computationally expensive shape-based docking method developed by Kuntz and co-workers or as a stand-alone method to rank compounds in a large database for their fit to a shape template. The merits and limitations of this method are discussed in detail with examples.

Ultrafast shape recognition to search compound databases for similar molecular shapes

“…However, histogram calculation has a number of well-known drawbacks, specially for very large databases, such as the difficulty of selecting a bin size suitable for all molecules in the database along with the requirement of relatively large storage and computing power. [16][17][18] These difficulties are circumvented by calculating instead the first moments of each of the four distributions of atomic distances in order to characterize them as a way to encode the molecular shape. Such approach is based on a theorem 30 from statistics, which proves that a distribution is completely determined by its moments.…”

“…There are a few methods that have followed this validation procedure to different extents. Nilakantan et al 17 presented the 10 molecules with the highest shape similarity score to a query out of 22, 498 in the database. The ranking (see Fig.…”

“…4 in ref. 17) presents some evident inconsistencies such as that of the molecule with the second highest score (BIWSIJ), which is very dissimilar from the rest of top ranked molecules, or that of the tenth highest score (BNOVCM), which should be higher in the ranking because it is visually more similar to the top ranked molecule that some molecules with higher score. Hahn 23 shows the 20 most similar molecules to Methotrexate for the presented superposition, hybrid grid-based method out of a database of 1,949,459 conformers.…”

“…The method has major weaknesses such as not being able to compare molecules with different number of atoms directly and requiring storage in some cases larger than that of the heavy atoms coordinates themselves. Nilakantan et al 17 presented another molecular shape comparison method based on atom triplets. Each molecule is represented by a condensed triplet shape signature.…”

Rapid Quantification of Molecular Diversity for Selective Database Acquisition

“…9 In both cases, the similarity between a pair of molecules is derived from the number of bits common to the bit-strings representing two molecules, using one of a range of available similarity coefficients, 10 and we have used this approach for all of the experiments reported here. However, the diversity measure is applicable to any situation in which a molecule is represented in vector form, e.g., by sets of topological indices 11,12 or calculated molecular properties.…”