Methods for identifying inhibitors against viruses that use a class I fusion protein
AssigneeJanssen Pharmaceuticals, Inc.
InventorsDirk André Emmy Roymans, Hendrik Leon Augusta Jozef De Bondt, Eric Pierre Alexandre Arnoult, Herman Van Vlijmen, Jean-François Bonfanti
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Abstract
The invention concerns the generation of a three dimensional model of the six helix bundle (6HB) complexed with an inhibitor and the use of that model to identify, screen and/or develop inhibitors against viruses that use a class I fusion protein. Such inhibitors of viruses that use a class I fusion protein may be effective for treating, for example, respiratory infections by Respiratory Syncytial Virus (RSV).
Claims8
A method for identifying an inhibitor against viruses that use a class I fusion protein comprising the steps of
- using the atomic coordinates of an alpha-helical coiled coil protein complex comprising amino acids Asp 194, Leu 195, Lys 196, Asn 197, Tyr 198, Asp 200, Lys 201, Gln 202, Leu 204, Ser 485, Asp 486, Glu 487, Phe 488, and Asp 489 according to FIG. 1±a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Angstrom to generate a three-dimensional structure of a molecule comprising an alpha-helical coiled coil protein complex binding pocket wherein said alpha-helical coiled coil protein complex binding pocket is a six-helix bundle (6HB);
- employing said three-dimensional structure to design or select said inhibitor wherein employing said three-dimensional structure to design or select an inhibitor comprises computationally performing a fitting operation between the computer model of the 6HB and the computer model of the inhibitor, and evaluating the results of the fitting operation to determine the ability of the inhibitor to interact with the 6HB and/or to characterize the interaction of the inhibitor with the 6HB;
- and
- contacting said inhibitor with a sample comprising an alpha-helical coiled coil protein complex and determining thereafter the ability of said inhibitor to bind to and inhibit an alpha-helical coiled coil protein complex activity characteristic for said viruses that use a class I fusion protein.
A method for identifying an inhibitor against viruses that use a class I fusion protein comprising the steps of
- using the atomic coordinates of an alpha-helical coiled coil protein complex comprising amino acids Tyr-198, Asp-200, Asp-486, Glu-487 and Phe-488 according to FIG. 1±a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å, to generate a three-dimensional structure of a molecule comprising an alpha-helical coiled coil protein complex binding pocket wherein said alpha-helical coiled coil protein complex binding pocket is a six-helix bundle (6HB);
- employing said three-dimensional structure to design or select said inhibitor wherein employing said three-dimensional structure to design or select an inhibitor comprises computationally performing a fitting operation between the computer model of the 6HB and the computer model of the inhibitor, and evaluating the results of the fitting operation to determine the ability of the inhibitor to interact with the 6HB and/or to characterize the interaction of the inhibitor with the 6HB;
- and
- contacting said inhibitor with a sample comprising an alpha-helical coiled coil protein complex and determining thereafter the ability of said inhibitor to bind to and/or inhibit an alpha-helical coiled coil protein complex activity characteristic for said viruses that use a class I fusion protein.
Dependencies are inferred from the claim text.