Open Access ChemVassa: A New Method for Identifying Small Molecule Hits in Drug Discovery

Abstract: ChemVassa, a new chemical structure search technology, was developed to allow rapid in silico screening of compounds for hit and hit-to-lead identification in drug development. It functions by using a novel type of molecular de-scriptor that examines, in part, the structure of the small molecule undergoing analysis, yielding its “information signa-ture. ” This descriptor takes into account the atoms, bonds, and their positions in 3-dimensional space. For the present study, a database of ChemVassa molecular descriptors was generated for nearly 16 million compounds (from the ZINC database and other compound sources), then an algorithm was developed that allows rapid similarity searching of the database using a query molecular descriptor (e.g., the signature of atorvastatin, below). A scoring metric then allowed ranking of the search results. We used these tools to search a subset of drug-like molecules using the signature of a commercially successful statin, atorvastatin (Lipitor™). The search identified ten novel compounds, two of which have been demonstrated to interact with HMG-CoA reductase, the macromolecular target of atorvastatin. In particular, one compound discussed in the results sec-tion tested successfully with an IC50 of less than 100uM and a completely novel structure relative to known inhibitors. In-teractions were validated using computational molecular docking and an Hmg-CoA reductase activity assay. The rapidity and low cost of the methodology, and the novel structure of the interactors, suggests this is a highly favorable new method for hit generation