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US 2004/0073375 A1Published application
Methods for identifying a molecule that may bind to a target molecule
OwnerJohn R. Hurstinventor
Life of this patent
Estimating the term…
Abstract
Methods which may be implemented in computer systems for screening a database of candidate molecules to determine whether any particular subset of candidate molecules may be docked to a target molecule. These methods determine the force field of a target molecule only once and may be used for screening a large number of candidate molecules.
Claims10
A method for determining if a candidate molecule is docked to a target molecule, the method comprising the steps of:
- a. determining a pseudo-energy function, E, between a target molecule and a candidate molecule for one or more of the possible positions Pi of each atom, i, comprising the candidate molecule;
- b. determining a function for the partial derivatives of E with respect to Pi for each atom i;
- c. determining an initial set of geometric parameters, Qj, describing the conformation of the candidate molecule;
- d. determining partial derivatives of Pi with respect to one or more of the Qj;
- e. determining the dot product of
- 25 ∂ E ∂ P i · ∂ P i ∂ Q j
- for one or more of the Qj;
- f. summing each dot product determined in part e over the i atoms comprising the candidate molecule, thereby determining partial derivatives of E as a function of the geometric parameters comprising the set Q;
- g. calculating a new set of geometric parameters based on the partial derivatives of E as a function of the geometric parameters calculated in step f;
- h. calculating a pseudo-energy for the candidate molecule with a conformation described by the new set of geometric parameters;
- i. if the pseudo-energy is less than a threshold energy, identifying the candidate molecule as docked;
- j. if the pseudo-energy is not less than a threshold energy, repeating steps d through j until a criteria is satisfied.
9 more elements
A method for determining whether a candidate molecule may be docked to a target, the method comprising the steps of:
- a. obtaining the three-dimensional coordinates for one or more atoms of a target molecule;
- b. determining a pseudo-energy function, E, between the target molecule and a candidate molecule for one or more of the possible position Pi of each atom, i, comprising the candidate molecule;
- c. determining a function for the partial derivative of E with respect to Pi for each atom i;
- d. obtaining the three-dimensional coordinates for each atom i of the candidate molecule;
- thereby determining the initial positions Pi for each atom of the candidate molecule;
- e. determining an initial set of geometric parameters, Qj, describing the conformation of the candidate molecule, where the set of geometric parameters comprises translational (T), rotational (R), and rotatable bond (B) parameters;
- f. determining partial derivatives of Pi with respect to the rotation and rotatable bond geometric parameters, using the equations:
- 27 ∂ P i ∂ R x = Di × ( 1 , 0 , 0 ) ∂ P i ∂ R y = Di × ( 0 , 1 , 0 ) ∂ P i ∂ R z = Di × ( 0 , 0 , 1 )
- where Di represents the vector connecting Pi to the rotational center, and
- 28 ∂ P i ∂ B b = μ b × D b , i
- where Db,i represents the vector connecting Pi to the end of the b'th rotatable bond, and
- μb is the unit vector along the b'th rotatable bond;
- g. determining the dot product of
- 29 ∂ E ∂ P i · ∂ P i ∂ Q j i ,
- for one or more of the Qj;
- h. summing each dot product determined in step g over the i atoms comprising the candidate molecule, thereby determining partial derivatives of E as a function of the geometric parameters comprising the set Q;
- i. calculating a new set of geometric parameters based on the set of geometric parameters and the partial derivative of E as a function of the geometric parameters calculated in step h;
- j. calculating a pseudo-energy for the candidate molecule with a conformation described by the new set of geometric parameters;
- k. if the pseudo-energy is less than a threshold energy, identifying the candidate molecule as docked;
- l. if the pseudo-energy is not less than a threshold energy, repeating steps f through l until a criteria is satisfied.
17 more elements
A method for screening a database of candidate molecules for docking with a target molecule comprising the steps of:
- a. obtaining the three-dimensional coordinates for one or more atoms of the target molecule;
- b. determining a pseudo-energy function, E, between the target molecule and one or more possible position Pk of each atom, k, contained in a set of atoms comprising all atoms contained in candidate molecules in a database of candidate molecules;
- c. determining a function of the partial derivative of E with respect to Pk for each atom k in the set of atoms;
- d. obtaining the three-dimensional coordinates for each atom i of a candidate molecule in the database of candidate molecules;
- thereby determining the initial positions Pi for each atom of the candidate molecule;
- e. determining an initial set of geometric parameters, Qj, describing the conformation of the candidate molecule, where the set of geometric parameters comprises translational (I), rotational (R), and rotatable bond (B) parameters;
- f. determining partial derivatives of Pi with respect to the rotational and rotatable geometric parameter using the equations:
- 31 ∂ P i ∂ R x = Di × ( 1 , 0 , 0 ) ∂ P i ∂ R y = Di × ( 0 , 1 , 0 ) ∂ P i ∂ R z = Di × ( 0 , 0 , 1 )
- where Di represents the vector connecting Pi to the rotational center, and
- 32 ∂ P i ∂ B b = μ b × D b , i
- where Db,i represents the vector connecting Pi to the end of the b'th rotatable bond, and
- μb is the unit vector along the b'th rotatable bond;
- g. determining the dot product of
- 33 ∂ E ∂ P i · ∂ P i ∂ Q j i ,
- for one or more of the Qj;
- h. summing each dot product determined in step g over the i atoms comprising the candidate molecule, thereby determining partial derivatives of E as a function of the geometric parameters comprising the set Q;
- i. calculating a new set of geometric parameters based on the partial derivatives of E as a function of the geometric parameters calculated in step h;
- j. calculating a pseudo-energy for the candidate molecule with a conformation described by the new set of geometric parameters;
- k. if the pseudo-energy is less than a threshold energy, identifying the candidate molecule as docked;
- l. if the pseudo-energy is not less than a threshold energy, repeating steps f through l until a criteria is satisfied.
- m. repeating steps e through 1 for each candidate molecule in the database of candidate molecules.
18 more elements
A system for determining if a candidate molecule is docked to a target, the system comprising:
- a processor;
- and
- a computer readable medium having computer readable program code means embodied therein for causing the system to identifying from a set of one or more candidate molecules one or more candidate molecules that may bind to a target molecule, the computer readable program code means comprising:
- (a) a computer readable program code means for causing a computer to carry out the step of determining a pseudo-energy function, E, between a target molecule and a candidate molecule for one or more of the possible positions Pi of each atom, i, comprising the candidate molecule;
- (b) a computer readable program code means for causing a computer to carry out the step of determining a function for the partial derivatives of E with respect to Pi for each atom i;
- (c) a computer readable program code means for causing a computer to carry out the step of determining an initial set of geometric parameters, Qj, describing the conformation of the candidate molecule;
- (d) a computer readable program code means for causing a computer to carry out the step of determining partial derivatives of Pi with respect to one or more of the Qj;
- (e) a computer readable program code means for causing a computer to carry out the step of determining the dot product of
- 35 ∂ E ∂ P i · ∂ P i ∂ Q j
- for one or more of the Qj;
- (f) a computer readable program code means for causing a computer to carry out the step of summing each dot product determined in part e over the i atoms comprising the candidate molecule, thereby determining partial derivatives of E as a function of the geometric parameters comprising the set Q;
- (g) a computer readable program code means for causing a computer to carry out the step of calculating a new set of geometric parameters based on the partial derivatives of E as a function of the geometric parameters calculated in step f;
- (h) a computer readable program code means for causing a computer to carry out the step of calculating a pseudo-energy for the candidate molecule with a conformation described by the new set of geometric parameters;
- (i) a computer readable program code means for causing a computer to carry out the step of identifying the candidate molecule as docked if the pseudo-energy is less than a threshold energy;
- and (j) a computer readable program code means for causing a computer to carry out the step of repeating steps d through j until a criteria is satisfied if the pseudo-energy is not less than a threshold energy.
12 more elements
An article of manufacture comprising a computer useable medium having computer readable program code means embodied therein for determining if a candidate molecule is docked to a target, the computer readable program code means comprising:
- (a) a computer readable program code means for causing a computer to carry out the step of determining a pseudo-energy function, E, between a target molecule and a candidate molecule for one or more of the possible positions Pi of each atom, i, comprising the candidate molecule;
- (b) a computer readable program code means for causing a computer to carry out the step of determining a function for the partial derivatives of E with respect to Pi for each atom i;
- (c) a computer readable program code means for causing a computer to carry out the step of determining an initial set of geometric parameters, Qj, describing the conformation of the candidate molecule;
- (d) a computer readable program code means for causing a computer to carry out the step of determining partial derivatives of Pi with respect to one or more of the Qj;
- (e) a computer readable program code means for causing a computer to carry out the step of determining the dot product of
- 36 ∂ E ∂ P i · ∂ P i ∂ Q j
- for one or more of the Qj;
- (f) a computer readable program code means for causing a computer to carry out the step of summing each dot product determined in part e over the i atoms comprising the candidate molecule, thereby determining partial derivatives of E as a function of the geometric parameters comprising the set Q;
- (g) a computer readable program code means for causing a computer to carry out the step of calculating a new set of geometric parameters based on the set of geometric parameters and the partial derivative of E as a function of the geometric parameters calculated in step f;
- (h) a computer readable program code means for causing a computer to carry out the step of calculating a pseudo-energy for the candidate molecule with a conformation described by the new set of geometric parameters;
- (i) a computer readable program code means for causing a computer to carry out the step of identifying the candidate molecule as docked if the pseudo-energy is less than a threshold energy;
- and (j) a computer readable program code means for causing a computer to carry out the step of repeating steps d through j until a criteria is satisfied if the pseudo-energy is not less than a threshold energy.
9 more elements
Dependencies are inferred from the claim text.