In silico Modeling
The in silico approach has been gaining traction in ADMETox research for the past five years. In silico tools enable researchers to do extensive modeling and virtual screening to generate a virtual ADMETox profile for thousands of compounds, eliminating poor candidates upfront. Actual assays are then performed from the short-listed pool of compounds, increasing the success rate of finding a good candidate with desirable ADMETox characteristics.
Bio-Rad (www.biorad.com) recently launched The KnowItAll Informatics System, Metabolomics Edition to aid in silico metabolomics research, which specifically focuses on the M and T of ADMETox.
The initial focus of the KnowItAll platform was analytical chemistry integrated with cheminformatics. At the end of 2003, Bio-Rad added in silico ADMETox prediction tools to this platform. “The new KnowItAll Metabolomics Informatics edition is empowered by the integration of Infometrix Pirouette chemometrics technology for multivariate analysis of NMR, spectrometry, and chromatography data,“ explains Gregory M. Banik, Ph.D., general manager of the informatics division.
The in silico modeling approach, using KnowItAll, needs to be initially validated against compounds with known experimental property values. Then, the models can be used for compounds for which experimental property values have not been measured to make predictions of the ADMETox characteristics or even build a virtual library for screening.
“Our platform offers several global models that can be used alone or together in a consensus fashion, which can decrease the error and increase the accuracy of prediction. It uses data mining and multivariate analysis tools that evaluate multiple endpoints simultaneously to rank order compounds, based on a composite score,“ states Dr. Banik. Bio-Rad plans to further enhance the ability to build and integrate local models in the KnowItAll system by integrating CSIROs (www.csiro.com) MolSAR molecular modeling technology.
“ADMETox in vitro testing has changed from an HTS approach to a more focused approach,“ comments Adrian Sheldon, Ph.D., associate director of the in vitro ADMET group at Charles River Laboratories (www.criver.com), which was another company discussing the topic at the IBC meeting. “However, the goals of in vitro ADME testing are still the same, that is rank order compounds for success and detect any compound issues.“
“We have several in vitro assays for determining drug-drug interactions,“ states Howard Haspel, Ph.D., study director of the In vitro ADMET group. “Under FDA guidelines, compounds require earlier testing for human specific metabolites. We have developed a broken cell method for rapid Phase I-Phase II metabolite profiling and species-specificity profiling that provides snapshot data in less than two weeks.
“Determining compound properties can be tricky and can result in unreliable data. We use integrated controls to assign a confidence score to potentially problematic compounds and support the results with other assay methods. ADMETox data generated by Charles River Laboratories have been used in over a dozen FDA IND filings by our clients,“ says Dr. Haspel.
ADMETRx offers in vitro ADME and physicochemical properties profiling along with consulting and integrative modeling approaches to pick the best bet compounds. It thus assists companies to make better compound fate decisions, based on an expert domain knowledge approach and a multicriteria decision-based strategy.
“The ADMETRx approach identifies and fills data gaps and integrates all this information to select optimal candidates for advancement,“ says Jay T. Goodwin, Ph.D., president & COO. ADMETRx addresses many of the challenges faced in drug discovery, such as achieving sufficient oral bioavailability, assessing CNS penetration, and evaluating potential for drug-drug interactions, while balancing these determinants with intrinsic activity, he maintains.
Peakdales (www.peakdale.co.uk) core expertise is innovative heterocyclic and medicinal chemistry. They use this approach coupled with computer-aided drug design to construct compounds with a superior starting point for drug discovery testing. Peakdale also offers chemogenetic arrays and collection of compounds designed to target receptors, families, enzymes, GPCRs, kinase library, and protease assays for enabling researchers in the ADMETox arena.
“Peakdale adopts a traffic light system—red, amber, or green representing outright issues, possible problems, or no problems respectively—to make a go-or-no-go decision for hit or lead compounds,“ says Terry Hart, Ph.D., director of medicinal chemistry services at Peakdale Molecular.
“Outright issues could be irreversible protein binding, mutagenic toxicity, herg, or apoptosis, while addressable problems could typically be due to bioavailability, Cyp inhibition, selectivity, or minor solubility issues. Hence, it is crucial to perform ADMETox profiling early in drug discovery so one is cognizant of what is ahead if a compound gets the go-ahead with possible problems.“
Caliper Life Sciences (www.caliperls.com) offers assay services and informatics tools through Novascreen Biosciences (www.novascreen.com). Novascreen recently announced the availability of General Side Effect II panel (GEN SEP II), a specialized side effect screening service that can be used with its Side Effect Database (SED).
The GEN SEP II assay panel spans a broad therapeutic range and encompasses a wide variety of molecular targets, including GPCRs, transporters, enzymes, nuclear receptors, ligand, and voltage-gated ion channels, to provide valuable information on a compounds efficacy and safety. The NovaScreen SED houses assay profiles through the same assay panel as the GEN SEP II on over 2,000 known biologically active compounds, like marketed/ failed/withdrawn drugs, reference agents, and natural products.
“The GEN SEP II and SED enable companies to map their compound in the context of the database to assist in identifying and eliminating side effect and safety concerns,“ says Seth Cohen, Ph.D., director of application sciences. “A key challenge is how to integrate and interpret data in a broader setting. This is where predictive ADMETox and in silico approaches are starting to live up to their potential.“