The BioSciences Group of Fujitsu unveils new in silico technique for enhanced ADME/Tox predictions

Westwood 12 July 2005The BioSciences Group of Fujitsu Computer Systems has unveiled a new technique for generating enhanced predictions for ADME/Tox research, consisting of a unique docking-based approach combined with off-the-shelf and purpose-built technologies, to develop viable and effective predictive models. The new approach was developed with a commercial collaborator focusing on drug-resistant infectious diseases and cancer.


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. Additionally, proprietary algorithms may create compliance issues and limit application to customer-specific work flows. Database approaches that focus on available literature are constrained by the efficiency of the literature curation process, which can be labour intensive.

Fujitsu has developed a technology and methods to overcome these limitations, and create a robust, in silico predictive platform for ADME/Tox. Fujitsu utilized several datasets to validate predictions, including the National Cancer Institute diversity datasets for initial calibrations and error estimates, and a proprietary database available from a commercial collaborator, to validate the in silico platform.

The ADME/Tox technique developed by the BioSciences Group consists of a computational work flow designed to build metabolite models, identify and model active sites, and then run the results 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.

To reduce the immense computational resources required to perform this work flow, the Fujitsu technique leverages hardware and software solutions to streamline and accelerate the process. The technologies involved and their role in the work flow include:

  • ADMEWorks: an ADAPT-based product used for testing initial model sets.
  • BioFrontier P450: a curated database for testing CYP interactions.
  • Neurosim L: a Neural Network programme to identify descriptors.
  • Support Vector Machine analyses: developed in R, used to classify and parse datasets.
  • Fujitsu in silico Screening platform (isS): high-throughput, high-precision computer simulation of protein-ligand docking and free energy of binding calculations using the BioServer Grid computing platform and proprietary simulation software.
  • Homology Modelling for Active Site Identification: utilizes sequence threading, multiple alignments and based on knowledgeable hashing protocols, for creating models of CYPs.
  • BioMedCAChe: a suite of predictive modelling tools used to visualize small molecules and active sites, and for running ActiveSite, which uses a docking algorithm based on an extended version of PMF.
  • Ligand Interaction Distance (LID) Score: developed in-house, utilizing matrices of bumps and bonds and MASCs, and used to quickly score docked configurations across target types.

"Developing and utilizing docking scores as descriptors provides biosciences researchers with a valuable and actionable metric for creating stronger predictive models", stated Takahiro Tsunekawa, vice president of the BioSciences Group. "Fujitsu has created a powerful technique to leverage existing technologies and solutions to reduce computational and work flow burdens that have made this type of research prohibitive in the recent past."

According to Dr. Michael J. McManus, vice president of Business Development for the BioSciences Group, "Conventional ADME/Tox black box approaches alone are not capable of telling researchers everything they need to know about the multifactorial processing involved in drug reaction in a living system. The Fujitsu view is that different problems are going to involve different levels of in silico modelling support and different amounts of wetlab validation."

He added: "The value of the Fujitsu approach is that it provides experimental 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 Fujitsu existing in silico screening technologies and processes, researchers can benefit from a practical and affordable technique."

The BioSciences Group, a division of Fujitsu Computer Systems Corporation, capitalizes on over 20 years of leadership from Fujitsu Limited in creating innovative and reliable solutions for helping experimental scientists overcome the challenges in their laboratory work flow. BioSciences Group solutions provide a framework for researchers to make in silico predictions about leads, targets, and interactions, and to validate these hypotheses experimentally.

BioSciences Group offerings include the CAChe suite of life sciences predictive modelling tools, the ActiveSite module for drug discovery lead-generation, and the BioServer massively parallel simulation server for genomics-based drug design.

Headquartered in Sunnyvale, California, Fujitsu Computer Systems is a wholly owned subsidiary of Fujitsu Limited committed to the design, development and delivery of advanced computer systems and managed services for the business enterprise. The company offers a complete line of high-performance mobile computers, scalable and reliable servers, storage, and middleware as well as managed and professional services. Fujitsu Computer Systems emphasizes leading-edge technology, exceptional product quality and user comfort and productivity, as well as outstanding customer service.

Fujitsu is a provider of customer-focused IT and communications solutions for the global marketplace. Pace-setting device technologies, highly reliable computing and communications platforms, and a worldwide corps of systems and services experts uniquely position Fujitsu to deliver comprehensive solutions that open up infinite possibilities for its customers' success. Headquartered in Tokyo, Fujitsu Limited reported consolidated revenues of 4,7 trillion yen or US$44,5 billion for the fiscal year ended March 31, 2005.

Leslie Versweyveld

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