Cadre is working with Professor David Ho and Professor Christopher Langmead to model the structural basis of Ibalizumab resistance. Dr. Ho's expertise lies in the prevention and treatment of HIV. His lab is working to develop novel vaccines as well as antibody based therapeutics. Of significant interest is the monoclonal antibody Ibalizumab, which is being developed for both prophylaxys and as a means of treatment. Ibalizumab blocks HIV infection through its interaction with the CD4 receptor and is now in clinical trials. Dr. Ho's lab is interested in modeling the molecular mechanism by which resistance to Ibalizumab can arise. Dr. Langmead is a pioneer in the development of physics-based methods for modeling, simulating, designing, and analyzing biomolecular interactions. Chris is modeling the molecular conformations assumed by the gp120-CD4-Ibalizumab complex to gain insight into the conformational differences between sensitive and resistant systems. Chris is also applying his statistics-based methods, GOBLIN and GREMLIN, to analyze residues which play a critical role in resistance.

 

Despite the importance of tool mark analysis in the forensic sciences, the imaging and comparison of tool marks remains a difficult and time consuming endeavor. Cadre is working with GelSight Inc and Todd Weller of the Oakland Police Department to develop a novel, accurate, and low-cost system for structural 3D imaging and comparison of cartridge cases and to demonstrate the system's potential for increasing the quality and reducing the cost of forensic analyses. GelSight is a 3D imaging technology based on the retrographic sensor of Johnson and Adelson (MIT) and has a resolution as low as 1 micron. The development of a GelSight based system will improve accuracy, reduce acquisition and operational costs, and shorten analysis time. We are working with federal and state forensics experts to complete product design and testing.

 

- Johnson, Cole, Raj, Adelson, SIGGRAPH, 2011.
- Johnson, Adelson, CVPR, 2009.

Cadre has partnered with University of California Irvine Computer Science professor Alexander Ihler and the industry leading cheminformatics company Optibrium to develop a novel algorithmic platform to improve the efficiency of High-Throughput Screening (HTS). In support of drug discovery, HTS has become a common technique for screening hundreds of thousands of compounds for potential binding to a target. Unfortunately HTS requires significant time and expense and is restricted by the chemical diversity of the library being screened. Traditionally, any cost savings realized by the reduction of screening library size results in a significant drop in the likelihood of success. We are developing techniques to address these concerns. Our algorithm combines computational ligand screening (i.e., docking) with multiple small batches of experimental wetlab testing. The method will identify hits in the compound library without the requirement that all compounds be screened experimentally. It will also tie into Optibrium's compound idea generation module, Nova, to generate and test derivative compound series. The resulting system will improve the coverage of HTS while reducing the required time and expense.

 

Cadre is working with Professors Chris Bailey-Kellogg and Karl Griswold at Dartmouth College to offer their suite of computational and experimental tools for producing immunotolerant variants of therapeutic proteins. Our methods integrate the computational prediction of T-cell epitopes and the bioinformatics-based assessment of the structural and functional consequences of epitope-deleting mutations. The approach is fundamentally different than traditional epitope predictors - our method both identifies and removes epitopes while maintaining molecular function. It does this by integrating validated immunoinformatics and structural modeling methods within a framework for identifying Pareto optimal designs. Our technology reduces the time and cost of removing T-cell epitopes; and will be of interest to any company working to mitigate potential anti-therapeutic immune responses. The model has been validated on several test systems.

 

- A.S. Parker, W. Zheng, K.E. Griswold, and C. Bailey-Kellogg, BMC Bioinf., 2010, 11:180.
- A.S. Parker, K.E. Griswold, and C. Bailey-Kellogg, J. Bioinf. Comp. Biol., 2011, 9:207.
- A.S. Parker, K.E. Griswold, and C. Bailey-Kellogg, Proc. RECOMB, 2012, 7262:184-198.

Cadre is working with the lab of Professor Bruce Donald at Duke University to develop and apply their structure-based computational methods for protein redesign. Their OSPREY software is specifically designed to identify protein mutants that possess desired target properties (e.g., improved stability, switch of substrate specificity). Most recently OSPREY has been extended to design protein-protein and protein-peptide interactions. The core methods incorporate multiple models of backbone and side-chain flexibility. It implements deterministic search via Dead-End Elimination (DEE) and A* based algorithms and evaluates candidate mutations using both ensemble (K*) and Global Minimum Energy scoring functions. Over the past eight years, these biophysically accurate methods have been validated on numerous biological systems. In addition to extending these techniques, Cadre offers a protein redesign service based on the methods developed in the Donald Lab. Please contact us for more information.

 

- Lilien, Stevens, Anderson, Donald, J Comp. Biol., 2004, 12(6):740-61.
- Georgiev, Lilien, Donald, Bioinformatics, 2006, 22(14):174-83.
- Georgiev, Keedy, Richardson, Richardson, Donald, Bioinformatics, 2008, 24(13):196-204.
- Gainza, Roberts, Donald, PLoS Comp. Biol., 2012, 8(1):e1002335.

For some reason, Cadre has become obsessed with the zebrafish. The zebrafish (Danio rerio) is emerging as an extremely valuable vertebrate model organism for developmental genetics and biomedical research. Much like the mouse, the zebrafish can serve as a model of human disease; however, compared to the mouse, working with the zebrafish is significantly easier and less expensive. These diploid vertebrates are small, easy to culture, have large completely transparent embryos, are easy to genetically manipulate, and develop quickly. Automated analysis of zebrafish behavior, phenotype, and morphology is still in the early stages. Cadre seeks industrial and academic collaborators to co-develop the next generation of experimental and computational zebrafish methods.