New technique enhances ADME/Tox predictions
ADME/Tox research could have new implications in developing novel
drug techniques in combating drug-resistant infectious diseases and
cancer.
The method is a docking-based approach combined with off-the-shelf and purpose-built technologies, to develop viable and effective predictive models. It works by using a computational workflow designed to build metabolite models, identify and model active sites.
The results are then run through a "high throughput docking" algorithm to dock the database of metabolites predicted against all Cytochrome P450 (CYP) models.
The end result of the process is a valuable metric for relative distances of docked configurations, to determine how much a compound and its derivative classes interact with differing CYP models.
Key challenges facing in silico ADME/Tox researchers include limitations in mathematical model approaches such as QSAR, and also in database-oriented approaches. QSAR approaches are often molecule-centric, poorly representing underlying biology.
As well as being sometimes difficult to validate or repeat, proprietary algorithms may create compliance issues and limit application to customer-specific workflows. Database approaches that focus on available literature are constrained by the efficiency of the literature curation process, which can be labour intensive.
Developers of the new technique, The BioSciences Group of Fujitsu Computer Systems, developed this predictive platform by utilising several datasets to validate predictions, including the National Cancer Institute diversity datasets for initial calibrations and error estimates.
"Developing and utilising docking scores as descriptors provides biosciences researchers with an actionable metric for creating stronger predictive models," said Takahiro Tsunekawa, vice president of the BioSciences Group.
"Fujitsu has leveraged existing technologies and solutions to reduce computational and workflow burdens that have made this type of research prohibitive in the recent past," he added.
Conventional ADME/Tox 'black box' approaches alone are not capable of telling researchers everything about the multifactorial processing involved in drug reaction in a living system. The view is that different problems are going to involve different levels of in silico modeling support and different amounts of wetlab validation.
Dr Michael McManus, vice president of Business Development for the BioSciences Group said: "The Fujitsu approach provides scientists with a model that allows them to get closer to the underlying biology, by providing a more 'complete' view of their research targets, as opposed to complex but limiting mathematical models."
"As this validation approach is built upon a foundation of in silico screening technologies and processes, researchers can benefit from a practical and affordable technique," he added.
