Crystal of a cytochrome-ligand complex and methods of use

A method for inhibiting activation of at least one procarcinogen, the method comprising:

• selecting an inhibitor of cytochrome P450 2A6 by performing a structure-based drug design using a three-dimensional structure determined for a crystal comprising a cytochrome P450 2A6 and a cytochrome P450 2A6 ligand;
• and
• contacting a sample or subject comprising a cytochrome P450 2A6 with the inhibitor.

A method for designing a drug which interferes with an activity of a cytochrome P450 2A6, the method comprising:

• (a) providing on a digital computer a three-dimensional structure of a cytochrome P450 2A6-ligand complex comprising the cytochrome P450 2A6 and a cytochrome P450 2A6 ligand;
• and
• (b) using software comprised by the digital computer to design a chemical compound which is predicted to bind to the cytochrome P450 2A6.

A crystal comprising a cytochrome P450 2A6 and a cytochrome P450 2A6 ligand.

A crystal comprising cytochrome P450 2A6 complexed with a cytochrome P450 2A6 ligand, wherein the crystal is sufficiently pure to determine atomic coordinates of the complex by X-ray diffraction to a resolution of about 2.05 Å.

A crystal comprising cytochrome P450 2A6 complexed with a cytochrome P450 2A6 ligand, wherein the crystal is sufficiently pure to determine atomic coordinates of the complex by X-ray diffraction to a resolution of about 1.90 Å.

A therapeutic compound which inhibits tobacco carcinogen activation by cytochrome P450 2A6, wherein the compound is selected by a) performing a structure based drug design using a three-dimensional structure determined for a crystal comprising cytochrome P450 2A6 and a cytochrome P450 2A6 ligand;

• b) contacting a sample comprising cytochrome P450 2A6 with the compound, and c) detecting inhibition of at least one activity of the cytochrome P450 2A6.

A three dimensional computer image of the three dimensional structure of a cytochrome P450 2A6-ligand complex, wherein the structure substantially conforms with the three dimensional coordinates listed in Table 1, Table 2, Table 4 or Table 5.

A computer-readable medium encoded with a set of three dimensional coordinates set forth in Table 1, Table 2, Table 4 or Table 5, wherein, using a graphical display software program, the three dimensional coordinates of Table 1, Table 2, Table 4 or Table 5 create an electronic file that can be visualized on a computer capable of representing said electronic file as a three dimensional image.

A computer-readable medium encoded with a set of three dimensional coordinates of a three dimensional structure which substantially conforms to the three dimensional coordinates represented in Table 1, Table 2, Table 4 or Table 5, wherein, using a graphical display software program, the set of three dimensional coordinates create an electronic file that can be visualized on a computer capable of representing said electronic file as a three dimensional image.

A method of forming a crystal comprising a cytochrome P450 2A subfamily member and a ligand of the cytochrome P450 2A subfamily member ligand, the method comprising:

• forming a composition comprising the cytochrome P450 2A subfamily member, the ligand, water and a non-ionic detergent;
• and
• adding a solution comprising ammonium sulfate and a polyethylene glycol to the composition.

A method for promoting cessation of tobacco smoking, the method comprising:

• selecting an inhibitor of cytochrome P450 2A6 by performing a structure based drug design using a three-dimensional structure determined for a crystal comprising the cytochrome P450 2A6 and a cytochrome P450 2A6 ligand;
• and
• administering an effective amount of the inhibitor to a human individual in need thereof.