US 7,065,453 B1Granted

Molecular docking technique for screening of combinatorial libraries

AssigneeAccelrys Software Inc.

InventorsDavid J. Diller, Kenneth M. Merz, Jr.

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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.

Claims2

Dependent claims

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;
selecting one or more optimized ligand positions based on said score;
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 bode 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;
and
wherein said determining the unique rigid body transformation comprises determining the unique rigid body transformation that minimizes:
I
⁡
(
R
,
T
)
=
∑
j
=
1
3
⁢
⁢

H
j
⁢
-
RA
j
-
T

2
where:
I(R,T)=rms deviation between a jth hot spot and a jth atom of the at least one solution conformation of the ligand;
Hj=a position vector of a jth hot spot of the protein;
Aj=a position vector of a jth atom of the at least one solution conformation of the ligand;
R=a 3×3 rotation matrix;
and
T=a translation vector.

43 more elements

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;
selecting one or more optimized ligand positions based on said score;
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;
and
wherein said determining the unique rigid body transformation comprises determining the unique rigid body transformation that minimizes:
I
⁡
(
R
,
T
)
=
∑
j
=
1
3
⁢
⁢

H
j
⁢
-
RA
j
-
T

2
where:
I(R,T)=rms deviation between a jth hot spot and a jth atom of the at least one solution conformation of the ligand;
Hj=a position vector of a jth hot spot of the protein;
Aj=a position vector of a jth atom of the at least one solution conformation of the ligand;
R=a 3×3 rotation matrix;
and
T=a translation vector.

43 more elements

Dependencies are inferred from the claim text.