New Database of Drug Metabolising Enzymes Relevant to Drug Development
Oct 28, 2009
Trinity College Researchers in collaboration with the US National Institutes of Health Chemical Genomics Center Create New Database of Drug-Metabolising Enzymes.
In their quest to find new and better drugs, researchers must weigh many factors, including the potentials of each compound to work effectively and to cause bad reactions. Among the most important factors to be considered are how a compound interacts with a family of liver enzymes, known as the cytochrome P450s (CYPs), that play an essential role in drug metabolism.
In an advance that should help speed drug discovery, researchers from Trinity College Dublin and the National Institutes of Health Chemical Genomics Center (NCGC) have generated the most comprehensive analysis to date of the CYP activity of thousands of drugs and possible drug candidates. Their study is published in the November 2009 issue of Nature Biotechnology.
CYPs, which come in 57 varieties, metabolise approximately two-thirds of drugs. However, just five of the CYPs handle 80 percent of these drugs. So, researchers set out to profile the interactions between these five CYPs and libraries of known drugs, along with several large libraries of chemical compounds, called small molecules, being screened for their potential as possible drugs.
“This database of drug metabolising enzymes will improve current models for predicting CYP-drug reactions and will be a resource for future testing in early phase drug discovery efforts,” said the study’s senior author, Dr Doug Auld, who is group leader for Genomic Assay Technologies at NCGC, which is administered by the National Human Genome Research Institute (NHGRI).
“It is only through collaborative ‘big science’ of this type and scale that we can really interrogate those molecular factors that are linked to cytochrome P450s (CYPs) metabolism and early drug failures. This data will help to steer future discovery campaigns in both industry and academia,” added Dr David Lloyd, Head of the Molecular Design Group at the School of Biochemistry and Immunology, Trinity College.
To conduct their study, the researchers used an approach developed at NCGC known as quantitative high-throughput screening (qHTS). This approach, which rapidly profiles compounds over a wide range of concentrations, is useful for generating large-scale bioactivity profiles of important gene families and for enabling the identification of chemical probes for use in biomedical research.
The researchers used qHTS to characterise CYP reactions in thousands of drugs and chemical compounds being screened drug discovery efforts. Past studies have only been able to address a few hundred compounds. In contrast, the NCGC study surveyed more than 17,000 compounds – each at seven or more different concentrations – against the five key metabolising enzymes.
The new data on CYP bioactivity is available to the worldwide research community through the free PubChem database (PubChem AID: 1851), which is managed by the National Library of Medicine.