Molecular docking technique for screening of combinatorial libraries

Abstract

A high-throughput molecular docking facility is presented for screening combinatorial libraries to identify binding ligands and ultimately pharmaceutical compounds. The facility employs a pre-docking conformational search to generate multiple solution conformations of a ligand. The molecular docking facility includes: generating a binding site image of the protein, the binding site image having multiple hot spots; matching hot spots of the binding site image to atoms in at least one solution conformation of the multiple solution conformations of the ligand to obtain at least one ligand position relative to the protein in a ligand-protein complex formation; and optimizing the at least one ligand position while allowing translation, orientation and rotatable bonds of the ligand to vary, and while holding the protein fixed.

1 . A computer-aided method of docking a ligand to a protein so as to determine ligand conformations likely to bind to said protein, said method comprising: 
 performing a pre-docking conformational search and generating multiple solution conformations of a ligand therefrom;    generating a binding site image of a protein, said binding site image comprising multiple hot spots;    matching hot spots of the binding site image to atoms in at least one conformation of the multiple solution conformations of the ligand to initially position said at least one conformation of said ligand as a rigid body into said binding site so as to obtain at least one position of the ligand relative to the protein in a protein-ligand complex;    optimizing the at least one position of the ligand while allowing translation, orientation and rotatable bonds of the ligand to vary, and while holding the protein fixed;    calculating a score for the optimized position of the ligand using one or more potential functions; and    selecting one or more optimized ligand positions based on said score.    
   
   
       2 . The method of  claim 1 , additionally comprising, after performing the pre-docking conformational search and generating multiple solution conformations, creating a database of the multiple solution conformations of the ligand and storing said three-dimensional database for subsequent use by said matching.  
   
   
       3 . The method of  claim 2 , wherein said database of the multiple solution conformations of the ligand comprises a conformational database of a combinatorial library.  
   
   
       4 . The method of  claim 1 , wherein said performing the pre-docking conformational search and generating multiple solution conformations of the ligand comprises: 
 randomly generating a plurality of conformations of the ligand;    minimizing the strain of each conformation of the plurality of conformations;    using the strain and the solvent accessible surface area of each conformation to rank the conformations; and    clustering the conformations and retaining a desired top number of clusters of conformations, said retained top number of clusters of conformations comprising said multiple conformations of the ligand in solution.    
   
   
       5 . The method of  claim 1 , wherein said generating the binding site image includes at least one of creating a list of apolar hot spots identifying points in the binding site that are favorable for an apolar atom to bind, and generating a list of polar hot spots identifying points in the binding site that are favorable for a hydrogen bond donor or acceptor to bind.  
   
   
       6 . The method of  claim 5 , wherein said generating the binding site image further comprises: 
 placing a grid around the binding site of the protein;    determining a hot spot search volume using said grid;    determining hot spots using a grid-like search of the hot spot search volume; and    for each type of hot spot, clustering the hot spots and retaining a desired number of top clusters of hot spots, said desired number of top clusters comprising said multiple hot spots to be employed by said matching.    
   
   
       7 . The method of  claim 1 , wherein said matching comprises: 
 matching atoms of the at least one solution conformation of the ligand to appropriate hot spots of the protein by positioning the at least one solution conformation of the ligand as a rigid body into the binding site image;    defining a match, said match determining a unique rigid body transformation; and    using the unique rigid body transformation to place the at least one solution conformation of the ligand into the binding site of the protein.    
   
   
       8 . At least one program storage device readable by a machine, tangibly embodying at least one program of instructions executable by the machine to perform a method of docking a ligand to a protein so as to determine ligand conformations likely to bind to said protein, said method comprising: 
 performing a pre-docking conformational search and generating multiple solution conformations of a ligand therefrom;    generating a binding site image of a protein, said binding site image comprising multiple hot spots;    matching hot spots of the binding site image to atoms in at least one conformation of the multiple solution conformations of the ligand to initially position said at least one conformation of said ligand as a rigid body into said binding site so as to obtain at least one position of the ligand relative to the protein in a protein-ligand complex;    optimizing the at least one position of the ligand while allowing translation, orientation and rotatable bonds of the ligand to vary, and while holding the protein fixed;    calculating a score for the optimized position of the ligand using one or more potential functions; and    selecting one or more optimized ligand positions based on said score.    
   
   
       9 . The at least one program storage device of  claim 8 , additionally comprising, after performing the pre-docking conformational search and generating multiple solution conformations of the ligand, creating a database of the multiple solution conformations of the ligand and storing said three-dimensional database for subsequent use by said matching.  
   
   
       10 . The at least one program storage device of  claim 9 , wherein said database of the multiple solution conformations of the ligand comprises a conformational database of a combinatorial library.  
   
   
       11 . The at least one program storage device of  claim 8 , wherein said performing the pre-docking conformational search and generating multiple solution conformations of the ligand comprises: 
 randomly generating a plurality of conformations of the ligand;    minimizing the strain of each conformation of the plurality of conformations;    using the strain and the solvent accessible surface area of each conformation to rank the conformations; and    clustering the conformations and retaining a desired top number of clusters of conformations, said retained top number of clusters of conformations comprising said multiple solution conformations of the ligand.    
   
   
       12 . The at least one program storage device of  claim 8 , wherein said generating the binding site image includes at least one of creating a list of apolar hot spots identifying points in the binding site that are favorable for an apolar atom to bind, and generating a list of polar hot spots identifying points in the binding site that are favorable for a hydrogen bond donor or acceptor to bind.  
   
   
       13 . The at least one program storage device of  claim 12 , wherein said generating the binding site image further comprises: 
 placing a grid around the binding site of the protein;    determining a hot spot search volume using said grid;    determining hot spots using a grid-like search of the hot spot search volume; and    for each type of hot spot, clustering the hot spots and retaining a desired number of top clusters of hot spots, said desired number of top clusters comprising said multiple hot spots to be employed by said matching.    
   
   
       14 . The at least one program storage device of  claim 8 , wherein said matching comprises: 
 matching atoms of the at least one solution conformation of the ligand to appropriate hot spots of the protein by positioning the at least one solution conformation of the ligand as a rigid body into the binding site image;    defining a match, said match determining a unique rigid body transformation; and    using the unique rigid body transformation to place the at least one solution conformation of the ligand into the binding site of the protein.    
   
   
       15 . The at least one program storage device of  claim 8 , wherein multiple positions of the ligand are obtained, and said optimizing step comprises: 
 eliminating each position of the ligand having a predetermined percentage of atoms with a steric clash;    ranking remaining positions of the ligand using an atom pairwise score with a desired atom score cutoff, said atom pairwise score comprising a hydrogen bonding potential score or a steric potential score;    after ranking, clustering the positions of the ligand and selecting a top number n of positions; and    optimizing each of the n positions, allowing the translation, orientation and rotatable bonds of the ligand to vary.    
   
   
       16 . The at least one program storage device of  claim 15 , wherein said optimizing comprises optimizing each position of the n positions using a Broyden-Fletcher-Goldfarb-Shanno (BFGS) optimization algorithm with said atom pairwise score, allowing the translation, orientation and rotatable bonds of the ligand to vary.