Research Scientist
Biotechnology and Bioengineering Department
(925) 294-3737 / dcroe@sandia.gov
Research Summary
My research focuses on simulations of molecular interactions using docking and molecular dynamics for applications in biodefense and biofuels.
Biodefense applications
- Identifying common functional sites to target for broad-based therapeutics.
- Virtual screening to identify lead therapeutics against bioagent threats.
- Identifying unique protein signatures to target for reagents in biodetectors.
Biofuel applications
- Protein engineering for the enhanced production of bioethanol.
Software
- PDock – docking code.
- PEngineer – protein engineering code.
- Common pocket – identify common sites across a range of targets.
Cellulase enzyme
Biodefense: Developing broad-based therapeutics against selected bioagents. To counter the full set of bioagent threats (both currently existing and those that can be genetically modified for drug resistance), it is important to develop new therapeutics that can bind to a broad range of possible agents with varying genetic sequences. By combining bioinformatics, high-thoughput homology modeling, and docking to predict binding profiles, we have developed tools to identify the functional subsites of target proteins that are highly conserved in their 3-D binding properties. After locating these sites, we apply virtual screening to find the lead compounds that bind to the broadest set of known strains/species in our target bioagent family.
Software Development
Dengue virus
- PDock. PDock, a suite of docking and combinatorial library codes, is written in C++ as an extensible platform to design and test new algorithms. PDock is built on Helgi Adalsteinsson’s PST library, a development environment that provides highly optimized parallel components for application development in particle simulations. For rigid docking and for its amber force-field scoring function with a ZAP solvation term, PDock uses the DOCK algorithm created by the University of California, San Francisco (UCSF). For flexible docking, PDock uses a Larmarkian evolutionary algorithm from the ACRO optimization library. Recent functionality added to PDock includes the addition of rotamer libraries for protein receptor flexibility (or peptide ligand) and the ability to dock to multiple protein structure variants simultaneously.
- PEngineer. This extension of the PDock software can model a combinatorial set of mutations to a given protein, thus optimizing the protein’s interactions with a substrate transition state.
- Common Pocket. This is part of the Common Motif and Countermeasure (CCM) algorithm jointly developed at Sandia and Lawrence Livermore National Laboratory. Common Pocket combines bioinformatic, structural, and pocket information to identify common functional pockets and subsites on proteins across a range of strains and related species. These pockets and subsites are then targeted for broad-spectrum binding.
- Builder and CombiBuild. I developed this software at UCSF for de novo drug design and combinatorial library optimization, respectively.
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- Protein Signature Evaluation (PSE) system: A high-throughput, whole-proteome, bio-informatics approach to protein target and signature discovery and characterization, U.S. patent pending.
- Methods and systems of common motif and countermeasure discovery, U.S. patent pending.
- Napthols useful in antiviral methods, U.S. patent number 6140368.
- Nonomolar, nonpeptide inhibitors of cathepsin D, U.S. patent number 6150415.
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- Ecale Zhou, CL, AT Zemla, D Roe, M Young, M Lam, JS Schoeniger, R Balhorn. (2005). Computational approaches for identification of conserved/unique binding pockets in the A chain of ricin. Bioinformatics 21:3089.
- Faulon, JL, D Visco, D Roe. (2005). Enumerating molecules. In Reviews in Computational Chemistry, Vol. 21, K Lipkowitz, R. Larter, TR Cundari, Eds. Wiley: Hoboken, NJ, pp. 209–215.
- Martin, S, D Roe, JL Faulon. (2005). Predicting protein–protein interactions using signature products. Bioinformatics 21:218.
- Springer, C, HA Adalsteinsson, MM Young, PW Kegelmeyer, DC Roe. (2005). PostDOCK: A structural, empirical approach to scoring protein ligand complexes. Journal of Medicinal Chemistry 48:6821.
- Wang, G, J De, JS Schoeniger, DC Roe, RG Carbonell. (2004). A hexamer peptide ligand that binds selectively to staphylococcal enterotoxin B: Isolation from a solid phase combinatorial library. Journal of Peptide Research 64:51-64.
- Cosman, M, FC Lightstone, VV Krishnan, L Zeller, MC Prieto, DC Roe, R Balhorn. (2002). Identification of novel small molecules that bind to two different sites on the surface of tetanus toxin C fragment. Chemical Research in Toxicology 15:1218.
- Skillman, AG, KW Maurera, DC Roe, MJ Staubera, D Earglea, TJA Ewing, A Muscatea, E Davioud-Charvetb, MV Medagliac, RJ Fisherc, E Arnoldd, H-Q Gaoe, R Buckheitf, PL Boyere, SH Hughese, ID Kuntza, G L Kenyon. (2002). A novel mechanism for inhibition of HIV-1 reverse transcriptase. Bioorganic Chemistry 30:443.
- Lightstone, FC, MC Prieto, AK Singh, MC Piqueras, RM Whittal, MS Knapp, R Balhorn, DC Roe. (2000). The identification of novel small molecule ligands that bind to tetanus toxin. Chemical Research in Toxicology 13:356.
- Roe, DC. (1999). Molecular diversity in site-focused libraries. In Molecular Diversity in Drug Design, PM Dean, RA Lewis, Eds. Klewer Academic Publishers: New York, pp. 141–174.
- Summers, JS, D Roe, PD Boyle, M Colvin, BR Shaw. (1998). Structural studies of a borane-modified phosphate diester linkage: Ab initio calculations on the dimethylboranophosphate anion and the single-crystal X-ray structure of its diisopropylammonium salt. Inorganic Chemistry 37:4158.
- Kick, EK, DC Roe [co-first authors], AG Skillman, G Liu, TJA Ewing, Y Sun, ID Kuntz, JA Ellman. (1997). Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D. Chemistry & Biology 4:297.
- Roe, DC, ID Kuntz. (1995). BUILDER v2: Improving the chemistry of a de novo design strategy. Journal of Computer-Aided Molecular Design 9:269.
- Roe, DC, ID Kuntz. (1995). What is structure-based drug design? Pharmaceutical News 2:13.
- Grootenhuis, PD, DC Roe, PA Kollman, ID Kuntz. (1994). Finding potential DNA-binding compounds by using molecular shape. Journal of Computer-Aided Molecular Design 8:731.
- Lewis, RA, DC Roe, C Huang, TE Ferrin, R Langridge, ID Kuntz. (1992). Automated site directed drug design using molecular lattices. Journal of Molecular Graphics 10:66.
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Ph.D., Pharmaceutical chemistry, the University of California, San Francisco, 1995. Research adviser: Tack Kuntz
B.S., Cellular and molecular biology, the University of Michigan, Ann Arbor, 1989.
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