NMR Crystallography Methods for Three-Dimensional Structure Determination

Abstract

The invention relates to new uses of nuclear magnetic resonance (NMR) crystallography methods to determine and/or characterize the three-dimensional structure of compounds of interest.

1 . (canceled) 
     
     
         2 . 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.   
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 2 , wherein the NMR values of reference compounds in (a) are obtained by experimental measurement or by calculation. 
     
     
         5 - 12 . (canceled) 
     
     
         13 . The method of  claim 2 , wherein the NMR values and atomic coordinates for equivalent atoms within said reference compounds are obtained from a database. 
     
     
         14 . 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.   
     
     
         15 . The method of  claim 14 , wherein the NMR values of reference compounds in (d) are obtained by experimental measurement or by calculation. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The method of  claim 2 , wherein said generated three-dimensional structure of said target compound is displayed. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . 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.   
     
     
         23 . The method of  claim 22 , wherein the NMR values of test compounds in (d) are obtained by experimental measurement or by calculation. 
     
     
         24 - 27 . (canceled) 
     
     
         28 . The method according to  claim 2 , wherein said NMR values are calculated or measured, or both calculated and measured, from one or more of the following types of interactions: Zeeman interactions, quadrupolar interactions, dipolar couplings, paramagnetic interactions, chemical shift, chemical shielding, and J-couplings. 
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 2 , further comprising calculating chemical shifts and chemical shielding for said generated three-dimensional structure and comparing the calculated chemical shifts and calculated chemical shielding to the chemical shifts and chemical shielding obtained by experimental measurement for said target compound. 
     
     
         31 . The method according to  claim 2 , further comprising refining said generated three-dimensional structure based on measurements obtained for said target compound by one or more of the following techniques: x-ray diffraction, neutron diffraction and electron diffraction. 
     
     
         32 - 34 . (canceled) 
     
     
         35 . The method according to  claim 2 , wherein the NMR values are obtained from a nuclear species in said target compound that is selected from the group consisting of:  13 C,  15 N,  17 O, and  31 P. 
     
     
         36 - 38 . (canceled) 
     
     
         39 . The method according to  claim 2 , further comprising refining said generated three-dimensional structure based on NMR values obtained for a second nuclear species in said target compound. 
     
     
         40 . The method according to  claim 2 , further comprising determining one or more additional crystallographic features of said target compound based on NMR values obtained for a second nuclear species in said target compound, wherein the one or more additional crystallographic features is selected from the group consisting of: unit cell parameters, space group, and long range order. 
     
     
         41 . The method according to  claim 2 , further comprising refining said generated three-dimensional structure based on NMR values calculated or measured, or both calculated and measured, from one or more of the following types of interactions: Zeeman interactions, quadrupolar interactions, dipolar couplings, paramagnetic interactions, chemical shift, chemical shielding, and J-couplings. 
     
     
         42 . The method according to  claim 2 , further comprising determining one or more additional crystallographic features of said target compound based on NMR values calculated or measured, or both calculated and measured, from one or more of the following types of interactions: Zeeman interactions, quadrupolar interactions, dipolar couplings, paramagnetic interactions, chemical shift, chemical shielding, and J-couplings, wherein the one or more additional crystallographic features is selected from the group consisting of: unit cell parameters, space group, and long range order. 
     
     
         43 - 45 . (canceled) 
     
     
         46 . The method according to  claim 2 , wherein said target compound has a molecular weight from about 100 to about 200,000 Daltons. 
     
     
         47 - 53 . (canceled) 
     
     
         54 . The method according to  claim 2 , wherein the method is automated. 
     
     
         55 - 61 . (canceled) 
     
     
         62 . The method of  claim 14 , wherein said generated three-dimensional structure of said target compound is displayed. 
     
     
         63 . The method according to  claim 14 , wherein said NMR values are calculated or measured, or both calculated and measured, from one or more of the following types of interactions: Zeeman interactions, quadrupolar interactions, dipolar couplings, paramagnetic interactions, chemical shift, chemical shielding, and J-couplings.