US 2003/0119061 A1 · Structure-based drug design methods for identifying D-Ala-D-Ala ligase inhibitors as antibacterial drugs

Abstract

The invention is based on the discovery that certain small molecules can bind to the ATP binding site of D-Ala-D-Ala ligase, even in the absence of the enzyme's substrate, and can cause a conformational change in the enzyme structure similar to that which occurs upon binding of ATP and substrate to the enzyme. Without wishing to be bound by any theory, it is believed that such a conformational change is required for either activation or inhibition of the enzyme. The information obtained from this discovery has enabled identification of key interactions in the active site of the enzyme, as well as the design and opimization of inhibitors.

Claims16

Dependent claims

A method for evaluating the potential of a chemical entity to associate with a molecule or molecular complex comprising a binding pocket defined by structural coordinates of D-Ala-D-Ala ligase E. coli amino acids Lys144, Glu180, Lys181, Leu183, Glu187, Asp257, and Glu270 according to FIG. 8;

or a homolog of said molecule or molecular complex, wherein said homolog comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than 10 Å comprising the steps of:
employing computational means to perform a fitting operation between the chemical entity and a binding pocket defined by structural coordinates of D-Ala-D-Ala ligase E. coli amino acids Lys144, Glu180, Lys181, Leu183, Glu187, Asp257, and Glu270 +/− a root mean square deviation from the backbone atoms of said amino acids of not more than 10 Å;
and
analyzing the results of said fitting operation to quantify the association between the chemical entity and the binding pocket.

1 more element

Dependencies are inferred from the claim text.

Structure-based drug design methods for identifying D-Ala-D-Ala ligase inhibitors as antibacterial drugs

Life of this patent

Structure-based drug design methods for identifying D-Ala-D-Ala ligase inhibitors as antibacterial drugs

Life of this patent

Abstract

Claims16