Pharmacogenic therapies targeting the metal-ion transcriptional regulation machinery in bacteria

摘要

The subject invention pertains to methods of identifying compounds that bind to a binding pocket on metal ion binding proteins of the ArsR/SmtB family and modulate their regulatory activity by increasing the propensity of the proteins to remain in a conformationally trapped form such as the metal ion bound conformation or disulfide-linked conformation, the DNA bound conformation, or the apo-conformation. The invention provides methods of identifying such compounds using computer software programs. The invention also provides bioassays for identifying such compounds. The invention also provides pharmaceutical compositions containing compounds that modulate metalloregulatory activities of the metal ion binding proteins of the ArsR/SmtB family.

主权项

1. A method of identifying a candidate compound that binds to a binding pocket of a protein of the ArsR/SmtB family of transcriptional factors, wherein, the regulatory protein exists in a first allosteric form, a second allosteric form, and an apo-form, wherein the first allosteric form is a conformationally restricted form (metal ion bound form or di-sulfide bound form) and the second allosteric form is a DNA bound form, and the apo-form is devoid of either the metal or the DNA,
the method comprising: providing a computer program with information comprising: a) structural information about a binding pocket of a protein of ArsR/SmtB family or metal ion transcriptional factors having similar allosteric mechanisms, b) structural information of the compound, and c) a set of rules and instructions about binding interactions between the compound and the binding pocket of the a protein belonging to the ArsR/SmtB family or metal ion transcriptional factors having similar allosteric mechanisms, wherein, based on the information and the instructions provided to the computer program, the computer program predicts whether the binding of the compound to the metal ion binding protein of ArsR/SmtB family or the metal ion transcriptional factor having similar allosteric mechanisms increases the propensity of the protein to remain in the metal ion bound form, the DNA bound form, or the apo-form, and selecting the compound if the propensity of the regulatory protein or the metal ion transcriptional factor to remain in the metal ion bound conformation, the DNA bound conformation, or the apo-conformation is higher when bound to the compound than the propensity of the protein or the metal ion transcriptional factor to remain in the metal ion bound conformation (or similar conformationally locked state), the DNA bound conformation, or the apo-conformation when not bound to the compound.