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Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4

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Abstract

Combinatorial synthesis and large scale screening methods are being used increasingly in drug discovery, particularly for finding novel lead compounds. Although these “random” methods sample larger areas of chemical space than traditional synthetic approaches, only a relatively small percentage of all possible compounds are practically accessible. It is therefore helpful to select regions of chemical space that have greater likelihood of yielding useful leads. When three-dimensional structural data are available for the target molecule this can be achieved by applying structure-based computational design methods to focus the combinatorial library. This is advantageous over the standard usage of computational methods to design a small number of specific novel ligands, because here computation is employed as part of the combinatorial design process and so is required only to determine a propensity for binding of certain chemical moieties in regions of the target molecule. This paper describes the application of the Multiple Copy Simultaneous Search (MCSS) method, an active site mapping and de novo structure-based design tool, to design a focused combinatorial library for the class II MHC protein HLA-DR4. Methods for the synthesizing and screening the computationally designed library are presented; evidence is provided to show that binding was achieved. Although the structure of the protein-ligand complex could not be determined, experimental results including cross-exclusion of a known HLA-DR4 peptide ligand (HA) by a compound from the library. Computational model building suggest that at least one of the ligands designed and identified by the methods described binds in a mode similar to that of native peptides.

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Author notes

  1. Erik Evensen

    Present address: Sunesis Pharmaceuticals, South San Francisco, CA, USA

  2. Gregory A. Weiss

    Present address: University of California, Irvine, CA, USA

Authors and Affiliations

  1. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA, USA

    Erik Evensen, Stuart L. Schreiber & Martin Karplus

  2. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Erik Evensen, Diane Joseph-McCarthy, Gregory A. Weiss, Stuart L. Schreiber & Martin Karplus

  3. Chemical and Screening Sciences Department, Wyeth Research, Cambridge, MA, USA

    Diane Joseph-McCarthy

  4. Howard Hughes Medical Institute, Cambridge, MA, USA

    Stuart L. Schreiber

  5. Laboratoire de Chimie Biophysique, ISIS, Université Louis Pasteur, 8 allée Gaspard Monge, 67000, Strasbourg, France

    Martin Karplus

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  2. Diane Joseph-McCarthy
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Correspondence to Diane Joseph-McCarthy or Martin Karplus.

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Evensen, E., Joseph-McCarthy, D., Weiss, G.A. et al. Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4. J Comput Aided Mol Des 21, 395–418 (2007). https://doi.org/10.1007/s10822-007-9119-x

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