Rhodium Docking Capability software enhances virtual screening capabilities for pharmaceutical, biochemical development

Jan 11, 2013
This three-dimensional structure shows the actual X-ray crystal structure of a cholinesterase enzyme. Shown in red is the crystallized form of the drug huperzine A, a possible treatment for Alzheimer's Disease. Shown in green are alternative poses of huperzine A, determined from Rhodium simulations. These poses suggest additional configurations visited by the drug molecule in the non-crystallized, biological form of the enzyme.

Southwest Research Institute (SwRI) has developed a unique software program that enables prescreening of the three-dimensional structure of proteins and enzymes for pharmaceutical and biochemical research prior to drug synthesis. Rhodium software, internally developed at SwRI and currently available for Institute client use, provides a more computationally efficient method of visualizing protein/small molecule complexes to expand pharmaceutical research and protein engineering capabilities.

"Rhodium represents a significant improvement in discovery by automatically searching the complete 3-D structure of a protein, without the intervention of an analyst," said Dr. Jonathan Bohmann, a senior research scientist in SwRI's Chemistry and Chemical Engineering Division. "This software, available currently for SwRI client use, accelerates drug discovery by rapidly screening feasible binding sites and docking (computer simulated) poses that are not revealed in crystal structures."

When designing a new drug, researchers must understand the extent to which a given drug or series of similar compounds (known as ligands) will bind with, or inhibit proteins. Rhodium can be used to interpret binding data from X-ray crystallography, a technique commonly used to obtain the three-dimensional structure of a drug ligand in a protein. Significant understanding can be obtained when crystals of the complex are grown and analyzed by X-ray crystallography. In some cases, crystallography reveals poses or the suggested positions of drug ligands in highly specific binding sites. X-ray crystallography has virtually no substitute in the process, but occasionally the interpretation of a is clouded by the presence of water and minor impurities in a drug. Some protein-ligand complexes are irregular or transient in nature, and definitive crystal structures can't be obtained. Rhodium can assist the analyst in these situations by ranking feasible poses of the ligand.

SwRI scientists can tailor Rhodium's search methods to individual research projects depending on client needs.

"Rhodium's capabilities are extensive compared with other docking programs," Bohmann said. "Our clients can benefit from these capabilities when working with us on pharmaceutical and biochemical research projects."

Rhodium provides a docking score and a ranking of the binding locations for possible drugs during the screening process. The program uses a hierarchical scoring system to search the entire protein, allowing researchers to find novel target sites or multiple binding sites.

The SwRI program generates a selection of ligand poses at each feasible site (such as the top 40 poses), which allows a researcher to extract the "top" pose for each site. This information is used to aid in the interpretation of experimental data, design new compounds or for biochemical engineering.

Through a joint internal research project between SwRI's Chemistry and Chemical Engineering and Automation and Data Systems Divisions, Rhodium's processing speed was recently accelerated by using enhanced capabilities in graphical processing unit (GPU) hardware. This development allows thousands of combinations of potential drug compounds and binding sites to be screened more efficiently and accurately.

Graphical Processing Units (GPUs) have evolved into General Purpose Graphical Processing Units (GPGPUs) that can now be used to accelerate non-graphical computation traditionally performed on Central Processing Units (CPUs), according to Automation and Data Systems Senior Research Analyst Steve Cook. "In certain cases, GPGPUs offer a lower cost and smaller footprint alternative to speed up computationally intensive parts of a program over cluster/supercomputing machines that are more expensive and more difficult to maintain," he said.

"By virtue of its ability to simultaneously rank several poses, Rhodium is useful to study competitive binding processes and guide synthesis of new ," Bohmann said.

and protein therapeutic research may benefit from the use of a software program such as Rhodium, according to Bohmann. When shifting the research focus from a ligand to its complementary protein, scientists can use Rhodium's features to optimize engineered mutations in a protein's makeup. The ability to design and test protein/small molecule combinations rapidly and efficiently accelerates recombinant protein engineering.

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More information: synchemistry.swri.org/

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