<b>Computer Simulation Of Molecular Docking To Screen Compounds</b><br/><br/>

Computer Simulation Of Molecular Docking To Screen Compounds

David Wilton

Introduction

Peptide fusion inhibitors based on C-helix regions of the human immunodeficiency virus (HIV) viral protein gp41 represent an important new class of antiviral therapeutics. However peptides are not ideal drugs. They are expensive to produce, have serious side-effects, and are difficult to take and administer. Researchers at Stony Brook University in New York are using computer simulations in conjunction with 3D stereographic methods to simulate and study the binding of peptide inhibitors which contain amino acid residues that pack into a conserved hydrophobic pocket on the surface of HIVgp41. Observations suggest that the gp41 pocket would be an ideal candidate for the design of small molecule therapeutics to treat HIV infection. A small molecule inhibitor of gp41 may have fewer side effects, be easier to administer, and be cheaper to produce than current therapies.

In an effort to identify a novel small drug-like molecule that could disrupt HIV, Dr. Robert C. Rizzo at Stony Brook University, in collaboration with experimentalist Dr. Miriam Gochin at Touro University College of Osteopathic Medicine in California, is using the computer simulation techniques of molecular docking to virtually screen molecular compounds from the National Cancer Institute and other available databases targeting the gp41 hydrophobic pocket. For each docked compound, the best-scoring complexes are ranked, clustered, and re-ranked using calculations which include more accurate estimates of desolvation. Finally, diversity selection, followed by visual inspection using 3D stereo graphics, of putative ligands is employed as filters for discovery of potential "lead" compounds. The most favorable compounds will be tested experimentally for their ability to bind to a gp41 pre-hairpin model using fluorescence and NMR-based assays.

Alternate frame sequencing

Figure 1. A close-up view of the target binding site on HIVgp41. C-helix residues (magenta) pack into a conserved hydrophobic pocket formed by two N-helices and a conserved salt bridge (Asp or Glu - Lys or Arg) is formed. Coordinates from pdb entry code 1IF3.

The 3D visualization method used in this research is alternate-frame sequencing or time sequential stereo with StereoGraphics CrystalEyes 3 liquid crystal display (LCD) shutter eyeglasses. LCD shutter eyeglasses use glass containing liquid crystal and a normally transparent polarizing filter that has the property of becoming dark when voltage is applied. The LCD eyeglasses are used in conjunction with the computer video card that is displaying the image of the 3D model, in this case an NVIDIA Quadro FX. An infrared emitter connected to the NVIDIA Quadro FX signals the LCD shutter eyeglasses to alternately apply voltage to the two eyepieces, darkening one then the other in synchronization with the refresh rate of the monitor, while the monitor alternately displays different perspectives for each eye. Since each eye only views half of the frames, a sufficiently high frame rate (96+ frames per second for the monitor or 48+ frames per second for each eye) is required to prevent the user from noticing flickering.

Molecular models and computer simulation results are viewed in 3D using software such as the Visual Molecular Dynamics (VMD) package and the Molecular Operating Environment (MOE) package. No special preparation or models are required for this visualization technique. The NVIDIA Quadro FX board manages the creation of the dual images, and full-color images produced by these packages can be viewed.

3D visualization is critical in three stages of the research. Visualization is important in defining the structure of the HIV simulations and setting up the docking (virtual screening) calculations. It is used to set up and visualize the simulations of peptides bound with gp41 using molecular dynamics. It is essential in the final screening to visualize the most tightly binding compounds to determine which ones are best. The ability to conduct this visualization at the researcher’s workbench is important for visualizing large numbers of potential compounds.

Conclusion

Figure 2. A representative compound (green) is evaluated for compatibility with the HIV binding site (gray) using NVIDIA Quadro stereo graphics.

Key to the wider adoption of 3D stereo visualization in similar applications is the relative low cost of the technique. Workstations equipped with appropriate NVIDIA Quadro graphics cards already exist in many laboratories. LCD shutter eyeglasses are required, but the cost is far less than that of the use of a complete 3D visualization studio. Further logistical savings are achieved through workflow efficiencies achieved by having visualization done at the bench, as opposed to in a separate visualization facility.

About the author

More information about the methods discussed in this article is available from David Wilton at dwilton@nvidia.com. More information about the research discussed in this article is available from Dr. Robert C. Rizzo at rizzo@ams.sunysb.edu.

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References

Cai, L.. and Gochin, M. A Novel Fluorescence Intensity Screening Assay Identifies New Low Molecular Weight Inhibitors of the gp41 Coiled Coil Domain of HIV-1. Antimicrobial. Agents and Chemotherapy. In press.

NVIDIA Corp. echnical Brief: 3D Stereo, Consumer Stereoscopic 3D Solution, 2003, TB-00252-001_v02.

Strockbine, B.; Rizzo, R. C., Binding of Anti-Fusion Peptides with HIVgp41 from Molecular Dynamics Simulations: Quantitative Correlation with Experiment. eins: Struct. Func. Bioinformatics 67:630-642 (2007).