Accounting for induced fit effects

Abstract

A system, device, and method for predicting a docked position of a target ligand in a binding site of a biomolecule is disclosed. The prediction makes use of a template ligand-biomolecule complex structure in order to predict a target ligand-biomolecule complex structure. The system and device contain modules allowing for the prediction of a target-ligand biomolecule complex structure. A preparation module can receive information identifying a target ligand and a template ligand-biomolecule structure. A pharmacophore matcher module can identify common pharmacophores between the template ligand and the target ligand. A docking module can predict a docked ligand position of the target ligand by overlapping the pharmacophore models of the target ligand and template ligand while the template ligand is in the binding site of the biomolecule. A biomolecule modification module can modify the biomolecule to reduce clashes between the docked target ligand and the biomolecule.

1 . Canceled 
     
     
         2 . A rational drug design method, comprising:
 identifying a plurality of candidate ligands for bonding to a biomolecular target, the target ligands being candidates for a drug associated with modifying a function of the biomolecular target;   predicting, using a computer system, a plurality of target ligand-biomolecule structures each comprising a corresponding candidate ligand of the plurality of candidate ligands and the biomolecular target with the corresponding candidate ligand being in a docked position in a binding site of the biomolecular target, each prediction comprising:
 receiving, by the computer system, a template ligand-biomolecule structure, the template ligand-biomolecule structure comprising a template ligand docked in the binding site of the biomolecular target; 
 comparing, using the computer system, a pharmacophore model of the template ligand to a pharmacophore model of the corresponding candidate ligand; 
 overlapping, using the computer system, the pharmacophore model of the corresponding candidate ligand with the pharmacophore model of the template ligand while the template ligand is in the binding site of the biomolecular target; and 
 predicting the docked position of the corresponding candidate ligand in the binding site of the biomolecular target based on a position of the pharmacophore model of the corresponding candidate ligand when overlapped with the pharmacophore model of the template ligand; and 
   providing, using the computer system, a ranked list of the plurality of candidate ligands.   
     
     
         3 . The method of  claim 2 , further comprising receiving a plurality of template ligand-biomolecule structures, each template ligand-biomolecule structure having a different template ligand docked in the binding site of the biomolecule, and generating the pharmacophore model of the template ligand by combining information from each of the template ligands from the plurality of template ligand-biomolecule structures. 
     
     
         4 . The method of  claim 2 , wherein at least one of the plurality of candidate ligands has more than one structural conformation in its unbound state, and the docked position of the correspond candidate ligand in the binding site of the biomolecule is predicted by enumerating a set of potential candidate ligand conformations and overlapping a respective pharmacophore model of the candidate ligand for each of the potential candidate ligand conformations with the pharmacophore model of the template ligand while the template ligand is in the binding site of the biomolecule. 
     
     
         5 . The method of  claim 4 , wherein predicting the docked position of the corresponding candidate ligand in the binding site of the biomolecule comprises ignoring at least one clash between the corresponding candidate ligand conformations' atomic coordinates and the biomolecule's atomic coordinates. 
     
     
         6 . The method of  claim 5 , further comprising, for each candidate ligand conformation, modifying atomic coordinates of the biomolecule to reduce clashes between the docked candidate ligand conformations' atomic coordinates and the biomolecule's atomic coordinates, thereby creating an altered ligand-biomolecule structure comprising the docked candidate ligand and an altered biomolecule. 
     
     
         7 . The method of  claim 6 , further comprising, predicting a re-docked position of each candidate ligand conformation by predicting each candidate ligand conformation's position in the binding site of the altered biomolecule; and
 for each candidate ligand conformation, modifying atomic coordinates of the altered biomolecule to reduce clashes between the atomic coordinates of the candidate ligand conformation's re-docked position and the atomic coordinates of the altered biomolecule, thereby creating a re-altered ligand-biomolecule structure comprising a re-docked candidate ligand and a re-altered biomolecule.   
     
     
         8 . The method of  claim 7 , wherein providing the ranked list comprises ranking each altered and re-altered ligand-biomolecule structure using a scoring function. 
     
     
         9 . The method of  claim 8 , wherein the providing the ranked list comprises identifying, using the computer system, a subset of high-ranking candidate ligands corresponding to candidate ligands having a threshold value for an empirical activity. 
     
     
         10 . The method of  claim 9 , wherein the ranked list of target ligands that includes the target ligand based on the predicted dock position and synthesizing one or more target ligands from the ranked list. 
     
     
         11 . The method of  claim 3 , further comprising selecting, based on the ranked list, one or more of the plurality candidate ligands for synthesis and assaying. 
     
     
         12 . The method of  claim 11 , further comprising synthesizing the one or more selected candidate ligands to provide one or more synthesized candidate ligands. 
     
     
         13 . The method of  claim 12 , further comprising performing at least one assay of the one or more synthesized candidate ligands. 
     
     
         14 . The method of  claim 13 , further comprising identifying a clinical candidate from the ranked list of candidate ligands based on the at least one assay. 
     
     
         15 . A computer system, comprising:
 at least one computer processor and a computer memory coupled to the at least one computer processor;   a preparation module, stored in the computer memory, wherein the preparation module is programmed to receive information identifying a plurality of candidate ligands and a template ligand-biomolecule structure comprising a template ligand and a biomolecule;   a pharmacophore matcher module, stored in the computer memory, wherein the pharmacophore matcher module is programmed to identify a pharmacophore match between the template ligand and each of the plurality of candidate ligands by comparing the pharmacophore model of the template ligand to the pharmacophore model of a corresponding candidate ligand of the plurality of candidate ligands; and   a docking module, stored in computer memory, wherein the docking module is programmed to predict, for the corresponding candidate ligand, a docked ligand position of the corresponding candidate ligand in the template ligand-biomolecule structure by overlapping the pharmacophore model of the corresponding candidate ligand with the pharmacophore model of the template ligand while the template ligand is in the binding site of the biomolecule; and   a ranking module, stored in the computer memory, wherein the ranking module is programmed to rank each altered ligand-biomolecule structure using a scoring function and output the ranked list.   
     
     
         16 . The computer system recited in  claim 15 , wherein the docking module is programmed to ignore at least one clash between the corresponding candidate ligand's atomic coordinates and the biomolecule's atomic coordinates when predicting the docked ligand position. 
     
     
         17 . The computer system recited in  claim 15 , further comprising a biomolecule modification module, stored in the computer memory, wherein the biomolecule modification module is programmed to modify atomic coordinates of the biomolecule to reduce clashes between the docked ligand position's atomic coordinates and the biomolecule's atomic coordinates, thereby creating an altered ligand-biomolecule structure having an altered biomolecule and a docked candidate ligand. 
     
     
         18 . The computer system recited in  claim 17 , wherein at least one of the candidate ligands have more than one structural conformation, and wherein the preparation module is programmed to enumerate a plurality of potential candidate ligand structural conformations for the at least one candidate ligand, and each of the enumerated potential candidate ligand structural conformations is processed by the docking module and the biomolecule modification module. 
     
     
         19 . A non-transitory computer readable storage medium comprising a computer readable program, wherein the computer readable program when executed on a computer causes the computer to rank a plurality of candidate ligands for selection for synthesis and assaying in a rational drug design method, the ranking being based on predicting a docked position for each of the plurality of candidate ligands in a binding site of a biomolecule, each prediction comprising causing the computer to perform the steps of:
 receiving information identifying a corresponding ligand of the plurality candidate ligands and a template ligand-biomolecule structure, using a preparation module stored in computer memory and coupled to at least one computer processor, the template ligand-biomolecule structure comprising a template ligand docked in the binding site of the biomolecule;   identifying a pharmacophore match between the template ligand and the corresponding candidate ligand, using a pharmacophore matcher module stored in the computer memory and coupled to at the least one computer processor, wherein the identifying of the pharmacophore match further comprises comparing a pharmacophore model of the template ligand to a pharmacophore model of the corresponding candidate ligand; and   predicting a docked ligand position of the target ligand, using a docking module stored in the computer memory and coupled to the at least one computer processor, wherein the docking module predicts the docked position of the corresponding candidate ligand in the binding site of the biomolecule based on a position of the pharmacophore model of the corresponding candidate ligand when overlapped with the pharmacophore model of the template ligand while the template ligand is in the binding site of the biomolecule.   
     
     
         20 . The computer readable storage medium as recited in  claim 19 , wherein the plurality of candidate ligands are selected from a candidate ligand database, each of the plurality of candidate ligands being different from the template ligand, and wherein selecting the plurality of candidate ligands comprises comparing the pharmacophore model of the template ligand to a pharmacophore model of each respective one of the plurality of candidate ligands. 
     
     
         21 . The computer readable storage medium as recited in  claim 19 , wherein the step of predicting an initial docked position comprises ignoring at least one clash between the corresponding candidate ligand's atomic coordinates and the biomolecule's atomic coordinates.