PDZ Drug Discovery Platform

Arbor Vita Corporation created the PDZ Drug Discovery Platform, which is used to discover PDZ domains or PDZ proteins that have the ability to interact with PDZ Ligands (PL). The PDZ Drug Discovery Platform offers exciting novel targeting, with the potential to create a new paradigm in drug discovery by reducing time and costs for target validation and drug screening and by increasing the quality of drugs (i.e., fewer side effects) and the overall probability of success. The Platform is a focused and rational approach to drug discovery, utilizing a combination of public and proprietary bioinformatics tools; in silico molecular modeling and virtual screening tools; a library of properly folded PDZ proteins; laboratory information management; and the company's high-throughput screening (HTS) PRISM Matrix assay. In preliminary screening, AVC has discovered over 1,200 novel interactions, each one a potential drug target.

Definitive PDZ Protein Reference Set

AVC has reduced the target discovery and validation process from months to days by creating a comprehensive, properly folded PDZ reference set. The reference set permits high-throughput screening for small-molecule drugs that will target any PDZ/PL interaction with specificity. The company has leveraged existing technology in a focused and rational approach to create the PRISM Database: the PDZ/PL reference set for drug discovery. Using information from the Human Genome Project, AVC has cloned and expressed nearly all the known human PDZ protein domains (approximately 330) into properly folded recombinant proteins to create a PDZ reference set. AVC has also created a comprehensive set of PLs and tested pair-wise combinations to create a reference set of PDZ/PL interactions. The proprietary PRISM Database contains all of the company’s experimental data including the PDZ and PDZ/PL reference sets.

Bioinformatics and In Silico Molecular Modeling

AVC has created a proprietary predictive bioinformatics tool that includes computer-based (in silico) molecular modeling that allows scientists to quickly assess the potential biochemical significance of each molecular interaction. Utilizing x-ray crystal structure information on PDZ proteins, the company has developed an accurate and testable set of computer models for PDZ domains. Using the experimental data in the PRISM Database, models of PDZ/PL complexes are used to direct small-molecule screens. Analysis of the data from such screens will allow AVC to further refine the docking models to reflect small-molecule binding. Validation of the in silico results can then be accomplished utilizing the company’s PRISM Matrix assay. To maximize value, the system is integrated with public and proprietary discovery research tools, relevant articles from the scientific literature, and other protein and nucleic acid databases.

AVC is also pioneering algorithms that permit biologists to conduct scientific queries in a more powerful, hypothesis-driven manner. These tools allow biologists without computer programming ability to generate and test ideas based on the most recent proprietary and public data. Combined with the power of the PDZ Drug Discovery Platform's biochemical assays, this bioinformatics and in silico approach makes it possible for the company to complete target identification and validation processes rapidly.

The PRISM Matrix HTS

The PRISM Matrix is a high throughput screen that uses properly folded human proteins to ensure that interactions identified via the PRISM Matrix HTS are true and relevant to actual biological systems. The PRISM Matrix HTS is rapidly scalable to meet both high-throughput therapeutic compound screening needs and partnership opportunities that may arise. The proprietary PRISM Matrix HTS quickly and accurately identifies novel interactions, titrates interactions to assess actual binding affinities and assesses the efficacy of potential lead compounds at blocking interactions. The PRISM Matrix HTS can be inexpensively automated with robotics, thus the capacity for expansion is virtually unlimited.