The SMD-Relaxed Complex Method for Drug Design

Summary

Principal Investigator: Rommie E Amaro
Abstract: [unreadable] DESCRIPTION (provided by applicant): The exploration of large-scale active site motions, and their affect on ligand discovery and optimization, is currently one of the most under-investigated areas in structure-based drug design. The proposed "SMD- relaxed complex" method addresses the challenge of increasing the receptor conformational space in a computationally efficient manner. Steered molecular dynamics simulations will be employed to remove a bound ligand from the receptor's active site, thereby accelerating the sampling of the receptor's conformational space. For receptors with deeply buried ligands or flexible loops, this technique could add significant insight into the prediction and evaluation of large domain motions and the effects of active site flexibility on inhibitor binding. The resulting receptor conformations will be ordered with the QR factorization algorithm, and the non-redundant, representative set of structures will be used to develop novel pharmacophore models and as input to the relaxed complex drug design protocol. The success of this new approach will be demonstrated on an essential RNA editing enzyme found in the trypanosomatid pathogens, which are responsible for several devastating tropical diseases. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-09-01 - 2009-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Remarkable loop flexibility in avian influenza N1 and its implications for antiviral drug design
    Rommie E Amaro
    Department of Chemistry and Biochemistry, NSF Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California 92093 0365, USA
    J Am Chem Soc 129:7764-5. 2007
  2. pmc Role of secondary sialic acid binding sites in influenza N1 neuraminidase
    Jeffrey C Sung
    Department of Chemistry, NSF Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California 92093, USA
    J Am Chem Soc 132:2883-5. 2010
  3. pmc A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology
    Jacob D Durrant
    Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America
    PLoS Comput Biol 6:e1000648. 2010
  4. pmc Emerging methods for ensemble-based virtual screening
    Rommie E Amaro
    Department of Pharmaceutical Sciences and Department of Information and Computer Science, University of California, Irvine, CA 92697, USA
    Curr Top Med Chem 10:3-13. 2010
  5. pmc Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective
    E Irene Newhouse
    Maui High Performance Computing Center, Kihei, Maui, Hawaii 96753, USA
    J Am Chem Soc 131:17430-42. 2009
  6. pmc Distinct glycan topology for avian and human sialopentasaccharide receptor analogues upon binding different hemagglutinins: a molecular dynamics perspective
    Dong Xu
    National Biomedical Computation Resource, University of California San Diego, La Jolla, CA 92093 0505, USA
    J Mol Biol 387:465-91. 2009
  7. pmc Characterizing loop dynamics and ligand recognition in human- and avian-type influenza neuraminidases via generalized born molecular dynamics and end-point free energy calculations
    Rommie E Amaro
    Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California 92093 0365, USA
    J Am Chem Soc 131:4702-9. 2009
  8. pmc AutoGrow: a novel algorithm for protein inhibitor design
    Jacob D Durrant
    Biomedical Sciences Program, University of California, San Diego, La Jolla, CA 92093 0365, USA
    Chem Biol Drug Des 73:168-78. 2009
  9. pmc Toward understanding the conformational dynamics of RNA ligation
    Robert V Swift
    Department of Chemistry and Biochemistry, NSF Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California 92093 0365, USA
    Biochemistry 48:709-19. 2009
  10. pmc Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei
    Rommie E Amaro
    Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA 92093 0365, USA
    Proc Natl Acad Sci U S A 105:17278-83. 2008

Detail Information

Publications16

  1. ncbi Remarkable loop flexibility in avian influenza N1 and its implications for antiviral drug design
    Rommie E Amaro
    Department of Chemistry and Biochemistry, NSF Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California 92093 0365, USA
    J Am Chem Soc 129:7764-5. 2007
  2. pmc Role of secondary sialic acid binding sites in influenza N1 neuraminidase
    Jeffrey C Sung
    Department of Chemistry, NSF Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California 92093, USA
    J Am Chem Soc 132:2883-5. 2010
    ..Our results indicate possible lowered HA activity for this secondary sialic acid site, which may be an important event in the emergence of the current pandemic strain...
  3. pmc A multidimensional strategy to detect polypharmacological targets in the absence of structural and sequence homology
    Jacob D Durrant
    Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America
    PLoS Comput Biol 6:e1000648. 2010
    ..As it is capable of identifying potential secondary targets, the strategy described here may play a useful role in future efforts to reduce drug side effects and/or to increase polypharmacology...
  4. pmc Emerging methods for ensemble-based virtual screening
    Rommie E Amaro
    Department of Pharmaceutical Sciences and Department of Information and Computer Science, University of California, Irvine, CA 92697, USA
    Curr Top Med Chem 10:3-13. 2010
    ..Finally, technological advances that will help make virtual screening tools more accessible to a wider audience in computer aided drug design are discussed...
  5. pmc Mechanism of glycan receptor recognition and specificity switch for avian, swine, and human adapted influenza virus hemagglutinins: a molecular dynamics perspective
    E Irene Newhouse
    Maui High Performance Computing Center, Kihei, Maui, Hawaii 96753, USA
    J Am Chem Soc 131:17430-42. 2009
    ..These results correlate well with existing experimental evidence, and suggest new opportunities for simulation-based vaccine and drug development...
  6. pmc Distinct glycan topology for avian and human sialopentasaccharide receptor analogues upon binding different hemagglutinins: a molecular dynamics perspective
    Dong Xu
    National Biomedical Computation Resource, University of California San Diego, La Jolla, CA 92093 0505, USA
    J Mol Biol 387:465-91. 2009
    ..Glycan composition and topological changes upon binding different HAs may be important determinants in species-specificity switch...
  7. pmc Characterizing loop dynamics and ligand recognition in human- and avian-type influenza neuraminidases via generalized born molecular dynamics and end-point free energy calculations
    Rommie E Amaro
    Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, California 92093 0365, USA
    J Am Chem Soc 131:4702-9. 2009
    ..We anticipate the findings presented here will have broad implications for the development of novel antiviral compounds against both seasonal and pandemic influenza strains...
  8. pmc AutoGrow: a novel algorithm for protein inhibitor design
    Jacob D Durrant
    Biomedical Sciences Program, University of California, San Diego, La Jolla, CA 92093 0365, USA
    Chem Biol Drug Des 73:168-78. 2009
    ..To validate AutoGrow, we recreate three crystallographically resolved ligands from their constituent fragments...
  9. pmc Toward understanding the conformational dynamics of RNA ligation
    Robert V Swift
    Department of Chemistry and Biochemistry, NSF Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California 92093 0365, USA
    Biochemistry 48:709-19. 2009
    ..Important features of RNA binding and specificity are revealed for kinetoplastid ligases and the broader nucleotidyltransferase superfamily...
  10. pmc Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei
    Rommie E Amaro
    Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA 92093 0365, USA
    Proc Natl Acad Sci U S A 105:17278-83. 2008
    ..These compounds are promising scaffolds for future drug design and discovery efforts against these important pathogens...
  11. pmc Ensemble-based virtual screening reveals potential novel antiviral compounds for avian influenza neuraminidase
    Lily S Cheng
    National Biomedical Computation Resource, University of California, San Diego, La Jolla, California 92093, USA
    J Med Chem 51:3878-94. 2008
    ..This ensemble-based VS and RCS approach may offer improvement over existing strategies for structure-based drug discovery...
  12. pmc Novel druggable hot spots in avian influenza neuraminidase H5N1 revealed by computational solvent mapping of a reduced and representative receptor ensemble
    Melissa R Landon
    Bioinformatics Graduate Program, Boston University, Boston, MA 02215, USA
    Chem Biol Drug Des 71:106-16. 2008
    ..Our hot spot analysis provides further support for the feasibility of developing high-affinity inhibitors capable of binding these regions, which appear to be unique to the N1 strain...
  13. pmc An improved relaxed complex scheme for receptor flexibility in computer-aided drug design
    Rommie E Amaro
    Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, 92093 0365, USA
    J Comput Aided Mol Des 22:693-705. 2008
    ..Finally, we outline potential methodological improvements that we anticipate will assist future development...
  14. pmc Functional and structural insights revealed by molecular dynamics simulations of an essential RNA editing ligase in Trypanosoma brucei
    Rommie E Amaro
    Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA
    PLoS Negl Trop Dis 1:e68. 2007
    ....
  15. pmc Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1
    Jacob D Durrant
    Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America
    PLoS Negl Trop Dis 4:e803. 2010
    ..RNA Editing Ligase 1 (REL1), a protein unique to trypanosomes and other kinetoplastids, was identified recently as a potential drug target...