Indexing Ultrafast Shape-Based Descriptors in MongoDB to Identify TLR4 Pathway Agonists

A method is presented for an ultrafast shape-based search workflow for the screening of large compound collections, i.e., those of vendors. The three-dimensional shape of a molecule dictates its biological activity by enabling the molecule to fit into binding pockets of proteins. Quite often, distinctly different chemical compounds that have similar shapes can bind in a similar way. OpenEye pioneered an algorithm for comparing shapes of molecules by overlaying them in a computer and measuring differences between a query molecule and a target molecule. Overlaying shapes is a computationally intensive process and represents a bottleneck in searching for similar molecules. More recent publications describe alternative methods of overlaying molecules, which are accomplished by comparing shape-based descriptors. These methods were implemented in the Open Drug Discovery Toolkit (ODDT) package. We utilized a combination of open-source software packages like ODDT and RDkit to implement a workflow for ultrafast conformer generation and matching that does not require storing precomputed conformers on the file system or in memory. Moreover, the generated descriptors could be optionally stored in MongoDB for performing searches in the future. To speed up the search, we created a set of indexes from the transformed shape-based descriptors. We are in the process of calculating descriptors for multiple vendors, including Enamine's "REAL" collection of 1.2 billion compounds. Currently, the shape similarity search on more than 70 million compounds takes less than 8 s! We exemplified our methodology with the screen of compounds that can act as putative TLR4 agonists. The search was based on a literature-known small-molecule TLR4 agonist series. In due course, we identified compounds with novel structural motifs that were active in mouse and human TLR4 reporter cell lines.