Session 8B
Drug Design as a Video Game: A Summer Program Integrating Chemical Biology and Computer Science Joseph P. Salisbury, Steven W. Morgan and John C. Williams, Jr.
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Abstract – Virtual drug screening is a rapidly evolving technique which offers great promise for the systematic evaluation of large chemical libraries to identify potential drug candidates. eHiTS Lightning is a commercial drug design software which takes advantage of the Cell Broadband Engine processor present in the video game console Sony PlayStation 3 to greatly accelerate computations. In the summer of 2008, a computational chemistry program for high school students was held at Rhode Island College which incorporated several different modules which combined biology, chemistry, and computer science. One of these modules focused on computer-aided drug design. Here, we describe the objectives, methods, achievements, and future goals of that aspect of the program where a high school student, mentored by a graduate student, used eHiTS Lightning on a Sony PlayStation 3 in order to identify molecules which may be potential cancer therapeutics. Index Terms – computer-aided drug design, molecular docking, virtual drug screening, protein-ligand interaction INTRODUCTION Computer-aided drug design (CADD) offers many opportunities for collaboration between computer scientists, biologists, and chemists. CADD encompasses the many processes necessary for organizing and accelerating the drug design process. In particular, virtual or in silico highthroughput screening can require a great deal of computing power in order to evaluate large chemical libraries that can be created and stored on computers. Processors such as the Cell Broadband Engine implemented in the Sony PlayStation 3 are capable of greatly increasing the rate of virtual screening as exemplified in eHiTS Lightning (SimBioSys, Toronto, Ontario) [1]-[2]. The use of a video game console for scientific computing not only has become a practical solution for obtaining results, but also adds to the appeal and creative possibilities of computational research for the upcoming generation. Beginning in the spring of 2008, a graduate student at Rhode Island College was given the task of developing a computer-aided drug design work-flow which could expand the capabilities of an organic chemistry laboratory carrying out drug development research. The emphasis was placed on
applying methods that were freely available through the Internet. However, the discovery of a virtual screening software, eHiTS Lightning, which was implemented on the Sony PlayStation 3 video game console offered an unique opportunity to broaden the appeal of computational chemistry research. After completing the design of a CADD work-flow which included eHiTS Lightning, the graduate student was given the opportunity to mentor a high school student as part of a larger summer program in computational chemistry being held at the college. The high school student completed a research project, the objective of which was to design small molecules that would be synthesized in the laboratory that were then tested as potential cancer therapeutics in collaboration with another university. The results of the high school student's project were presented at several national scientific conferences and the high school student continues work on the project into his college career. As stated, the objective of the high school student's project was to design small molecules that could be tested as cancer therapeutics. More specifically, the small molecules evaluated were of several varieties that the laboratory was synthesizing. In achieving this objective, the project offered the opportunity for the high school student to learn basic concepts in organic chemistry including the possible structures organic molecules can have and how they can be functionalized. Furthermore, the student learned the basic biology behind how the small molecules would interact with a protein in order to possibly treat cancer. Finally, the student learned the basics of scripting and operating the command line in Linux, the operating system available on the Sony PlayStation 3, in order to fulfill the primary objective of the project. Thus, we see the interdisciplinary nature of this project and how it offers the opportunity to combine knowledge and skills in the areas of biology, chemistry, and computer science in order to complete a single, over-arching goal. In completing the project, the student designed (see Methods section) several libraries of compounds on the computer under the guidance of the graduate student mentor which were evaluated using eHiTS Lightning. The molecules were “docked” or fitted into a specific pocket on the structure of the estrogen receptor, a popular target for breast cancer therapeutics such as tamoxifen, using the software. Molecules that scored high, that is, were predicted by the software to interact with the estrogen receptor
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Session 8B strongly, were prioritized as compounds the lab should synthesize in the future. Here, we describe the methods used by the high school student in order to generate and test compounds as possible cancer therapeutics in the Methods section. We further describe the results of this research project in the Results section, as well as offer additional ideas on how to expand this project for other students in the Discussion section. METHODS Several “scaffolds” or essential parts of several molecules were chosen based on the capabilities of the laboratory to synthesize specific compounds. The scaffold was drawn using the freely available online program Molinspiration WebME [3]. The SMILES representation [4] of a given molecule, a string which stores the connectivity information of the molecule, was obtained using the program so that the structure of the molecule could be transferred to other programs. In particular, the SMILES string was then entered into the program SmiLib [5]-[6] which was used to generate combinatorial libraries of molecules based around a specific scaffold. Functional groups were also drawn using WebME and transferred into SmiLib so that SmiLib could generate libraries with specified combinations of functional groups. The combinatorial library generated by SmiLib is stored in a text file which can be opened using several programs so that the molecules contained in the file can be viewed. In order for the molecular libraries to be evaluated using eHiTS Lightning, the molecules must be converted from the SMILES format (which only contains information about the atoms which make up molecules and their connectivity) to a 3D format which places the atoms at specific locations based on the results of some energy minimization algorithm. Frog [7] is a freely available web server that can generate three dimensional representations of molecules for virtual drug screening from the SMILES format. Upon obtaining a file containing 3D representations of the molecular library, the compounds are now ready for virtual screening using eHiTS Lightning. Alternatively, prior to or immediately after converting compounds to 3D format, the compound library can be screened for druglikeliness in order to eliminate molecules that would not make good drug candidates. This can greatly reduce the size of a library that might be rather large after combinatorial generation. In order to screen compounds for druglikeliness. FAF-Drugs [8]-[9] is one freely available Internet-based program that can screen libraries based on an array of parameters. Including this step also allows for the student to learn the basics of medicinal chemistry, specifically, what makes certain compounds more favorable as drugs than others. Upon obtaining a library of molecules in 3D format, it is necessary to also obtain a 3D structure of a protein that we hope the molecules we designed will interact with favorably. 3D structures of proteins are freely available through the Protein Data Bank [10]. For many popular drug targets, several different structures of the same protein are available
allowing for comparisons to be made for which structure may give the most reliable results. In order to determine the capacity for virtual screening software such as eHiTS to accurately predict the binding strength of small molecules for a protein target, a test set of molecules can be obtained from the BindingDB [11] that are known to interact with the protein target. A structure can be chosen which gives the best scores for the test molecules known to interact with the protein and not for a set of decoy molecules known not to interact with the protein of choice. Results can be viewed using several programs including PyMol. CheVi (SimBioSys) can be used directly on the Sony PlayStation 3 when operating in Linux. An overview of the method described here can be seen in Figure 1.
FIGURE 1 AN OVERVIEW OF THE DRUG SCREENING PROCESS USED IN OUR PROJECT
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Session 8B RESULTS Overall, this research project was successful in obtaining its objectives of enhancing education at the interface between biology, chemistry, and computer science. The results of the research project completed by the high school student were presented at several regional and national scientific conferences including the 2008 National IDeA Symposium of Biomedical Research Excellence, the 2008 MERCURY Conference on Computational Chemistry, the 2008 Northeast Regional Undergraduate and Graduate Student Sigma Xi Conference, and the 2010 American Chemical Society National Conference. In tandem with the research being completed by the high school student, the graduate student mentor completed a research project of his own using the method described, which resulted in a publication [12]. The high school student, who is now an undergraduate, continues to complete research for the laboratory in a continued effort to design potential cancer therapeutics. DISCUSSION We have attempted to show that CADD offers an exciting opportunity for research projects that attempt to promote interaction among biology, chemistry, and computer science. In particular, CADD using software optimized for the Sony PlayStation 3 provides a unique educational tool with great potential that has still not fully been explored. We have installed drivers on to the Sony PlayStation 3 running Linux so that it is possible to use the game controller to manipulate molecules in CheVi, creating a more interactive experience for visualizing and inspecting results. We imagine it would also be possible to find a way to use more recently introduced peripheral devices for the Sony PlayStation 3 such as the PlayStation Move to produce even more dynamic ways of interacting with three-dimensional molecular structures. Furthermore, we have not considered other scientific computing software which may also benefit from the processing capabilities of the Sony PlayStation 3. Other research projects could include evaluating whether running various programs on the Sony PlayStation 3 may be beneficial. Already, numerous scientific computing programs have been tested on the Sony PlayStation 3 [13][16]. Combining scientific computing programs with the interactive capabilities of the Sony PlayStation 3 may offer many opportunities for fun and creative educational projects. ACKNOWLEDGMENT This work was supported by operating grants from the Rhode Island Science and Technology Advisory Council (RIRA #2008-44), the Rhode Island IDeA Network of Biomedical Research Excellence (5P20RR016457-07), and the RI Board of Governors for Higher Education (Grant
Appropriation Account #108528051072). The authors would also like to thank SimBioSys Inc. for letting us beta test eHiTS Lightning. REFERENCES [1] [2] [3] [4]
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Zsoldos, Z., Reid, D., Simon, A., et al., "eHiTS: An Innovative Approach to the Docking and Scoring Function Problems,” Current Protein and Peptide Science, Vol 7, No 5., 2006, pp. 421-435. Zsoldos, Z., Reid, D., Simon, A., et al., "eHiTS: A new fast, exhaustive flexible ligand docking system,” Journal of Molecular Graphics and Modelling, Vol 26, 2007, pp. 198-212. http://www.molinspiration.com/docu/webme/ Weininger, D., "SMILES, a Chemical Language and Information System. 1. Introduction to Methodology and Encoding Rules,” Journal of Chemical Information and Computer Sciences, Vol 28, No 1., 1988, pp. 31-36. Schüller, A., Schneider, G., Byvatov, E., "SMILIB: Rapid Assembly of Combinatorial Libraries in SMILES notation,” QSAR & Combinatorial Science, Vol 22, 2003, pp. 719-721. Schüller, A., Hähnke, V., Schneider, G., "SmiLib v2.0: A Java-Based Tool for Rapid Combinatorial Library Enumeration,” QSAR & Combinatorial Science, Vol 26, No 3., 2007, pp. 407-410. Leite, T. B., Gomes, D., Miteva, M. A., et al., "Frog: a Free Online drug 3D conformation generator,” Nucleic Acids Research, Vol 35, 2007, pp. W568-W572. Miteva, M. A., Violas, S., Montes, M., et al., "FAF-Drugs: free ADME/tox filtering of compound collections,” Nucleic Acids Research, Vol 34, 2006, pp. W738-W744. Lagorce, D., Sperandio, O., Galons, H., et al., "FAF-Drugs2: Free ADME/tox filtering tool to assist drug discovery and chemical biology projects,” BMC Bioinformatics, Vol 9, No 396, 2008. http://www.pdb.org/ Liu, T., Lin, Y., Wen, X., et al., "BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities,” Nucleic Acids Research, Vol 35, 2007, pp. D198-D201. Salisbury, J. P., Williams, J. C., "Docking study of triphenylphosphonium cations as estrogen receptor alpha modulators,” Bioinformation, Vol 3, No 7, 2009, pp. 303-307. Nomura, K., de Leeuw, S. W., Kalia, R. K., et al., "Parallel Lattice Boltzmann Flow Simulation on A Low-Cost PlayStation 3 Cluster,” International Journal of Computational Science, Vol 2, No 4, 2008, pp. 437-449. Narumi, T., Kameoka, S., Taiji, M, et al., "Accelerating Molecular Dynamics Simulations on PlayStation 3 Platform Using VirtualGRAPE Programming Model,” SIAM Journal on Scientific Computing, Vol 30, 2008, pp. 3108-3125. Sevre, E. O. D., Christiansen, M. D., Broten, M., et al., "Experiments in scientific computation on the PlayStation 3,” Visual Geosciences, Vol 13, No 1, 2008, pp. 125-132. Gwosdek, P., Bruhn, A., Weickert, J., "Variational optic flow on the Sony PlayStation 3,” Journal of Real-Time Image Processing, Vol 5, No 3, 2010, pp. 163-177.
AUTHOR INFORMATION Joseph P. Salisbury, PhD Candidate, Neuroscience Program, Brandeis University. Steven W. Morgan, Undergraduate, Rhode Island College. John C. Williams, Jr., Professor, Physical Sciences Department, Rhode Island College.
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