In Silico Enzymatic Synthesis of a 400 000 Compound Biochemical Database for Nontargeted Metabolomics

Current
methods of structure identification in mass-spectrometry-based
nontargeted metabolomics rely on matching experimentally determined
features of an unknown compound to those of candidate compounds contained
in biochemical databases. A major limitation of this approach is the
relatively small number of compounds currently included in these databases.
If the correct structure is not present in a database, it cannot be
identified, and if it cannot be identified, it cannot be included
in a database. Thus, there is an urgent need to augment metabolomics
databases with rationally designed biochemical structures using alternative
means. Here we present the In Vivo/In Silico Metabolites Database
(IIMDB), a database of in silico enzymatically synthesized metabolites,
to partially address this problem. The database, which is available
at http://metabolomics.pharm.uconn.edu/iimdb/, includes ∼23 000 known compounds (mammalian metabolites,
drugs, secondary plant metabolites, and glycerophospholipids) collected
from existing biochemical databases plus more than 400 000
computationally generated human phase-I and phase-II metabolites of
these known compounds. IIMDB features a user-friendly web interface
and a programmer-friendly RESTful web service. Ninety-five percent
of the computationally generated metabolites in IIMDB were not found
in any existing database. However, 21 640 were identical to
compounds already listed in PubChem, HMDB, KEGG, or HumanCyc. Furthermore,
the vast majority of these in silico metabolites were scored as biological
using BioSM, a software program that identifies biochemical structures
in chemical structure space. These results suggest that in silico
biochemical synthesis represents a viable approach for significantly
augmenting biochemical databases for nontargeted metabolomics applications.