NMR Crystallography Methods for Three-Dimensional Structure Determination

A method for determining the three-dimensional structure of a target compound by nuclear magnetic resonance (NMR) crystallography, said method comprising:

• (a) identifying a set of reference compounds from existing molecules which have known three-dimensional structure and which comprises similar substructures present in said target compound;
• (b) obtaining NMR values for said target compound and both NMR values and atomic coordinates for equivalent heavy atoms within said reference compounds;
• (c) selecting a subset of reference compounds based upon the most suitable calculated relevant statistical match (rsm) for equivalent heavy atoms in each reference compound identified in (a);
• and
• (d) obtaining and compiling the atomic coordinate data for equivalent heavy atoms of reference compounds selected in (c) to generate a three-dimensional structure of said target compound.

A method for determining the three-dimensional structure of a target compound, said method comprising:

• (a) obtaining a two-dimensional drawing of said target compound, NMR values of a preselected nuclear species contained within said target compound, and a database that comprises both NMR values of the same preselected nuclear species and atomic coordinate data for reference compounds;
• (b) selecting a first heavy atom of said target compound;
• (c) generating a substructure of said target compound that includes all other heavy atoms within said target compound that are separated by no more than 3 chemical bonds from said heavy atom;
• (d) identifying a set of reference compounds from existing molecules which have known three-dimensional structure and which comprises the identical substructure generated in (c) in said database;
• (e) calculating root mean square values for each of the reference compounds identified in (d);
• (f) selecting from the reference compounds identified in (d), the reference compound having the lowest calculated rms value;
• (g) obtaining the atomic coordinate data for the equivalent heavy atom of the selected reference compound of (f);
• (h) repeating (c)-(g) for each of the remaining heavy atoms of said target compound;
• and
• (i) compiling all of the atomic coordinate data obtained in (g) to generate a three-dimensional structure of said target compound.

A method of screening for test compounds having three-dimensional structures similar to that of a target compound, said method comprising:

• (a) providing two-dimensional drawings of said test compounds, NMR values of a preselected nuclear species contained within said test compounds, NMR values of the same preselected nuclear species for said target compound, and atomic coordinate data for said target compound;
• (b) selecting a first heavy atom of said target compound;
• (c) generating a substructure of said target compound that includes all other heavy atoms within said target compound that are separated by no more than 3 chemical bonds from said heavy atom;
• (d) identifying a set of test compounds comprising substructures similar to the target compound substructure generated in (c);
• (e) calculating root mean square values for each of the test compounds identified in (d);
• (f) selecting from the test compounds identified in (d), the test compound having the lowest calculated rms value;
• (g) repeating (c)-(f) for each of the remaining heavy atoms of said target compound;
• (h) calculating global rms values for each of the test compounds selected in (f);
• and
• (i) selecting from the test compounds identified in (f), the test compound having the lowest calculated global rms value.