Binding affinity scoring function penalizing compounds which make unfavorable hydrophobic contacts with localized water molecules in the receptor active site
First Claim
1. A method of scoring binding affinity of a proposed ligand molecule for a receptor molecule using a sufficiently programmed computer for the following steps:
- a. obtaining computer stored data representing a predicted ligand-receptor structure,b. determining whether the receptor alone, without a docked ligand, includes one or more hydration sites occupied by localized water, and, if so,c. determining if after docking a receptor-localized water interacts with a hydrophobic ligand atom, and if the docking of the ligand into the receptor results in unfavorable interaction of the ligand with a localized water molecule occupying a receptor hydration site,d. determining whether one or more of the exceptions conditions i.-iv. is present;
i. the hydrophobic ligand atom has a net positively charged ligand atom positioned a distance of 4 atoms or fewer from the hydrophobic ligand atom, where the distance is determined by bond connectivity of the atoms in the ligand;
ii. the hydrophobic ligand atom that is part of a ligand —
CH3 group, or a ligand atom within 3 atoms of a —
CH3 group, where the localized water borders the edge of a hydrophobic pocket giving it access to surrounding water;
iii. the localized receptor water is positioned within 5 Å
of a positively charged ligand atom;
iv. the localized receptor water has hydrogen bonds to the ligand;
e. applying a penalty to scoring function of binding affinity if
1) the localized receptor water interacts with a hydrophobic ligand atom as determined in step c, and
2) none of the exception conditions i. iv. is present.
3 Assignments
0 Petitions
Accused Products
Abstract
A method of scoring binding affinity of a proposed ligand molecule for a receptor molecule using a computer and computer data bases, which accounts for the increase in energy required where docking disrupts water molecules that are localized at ligand hydration sites. The method uses computer-stored data representing a predicted ligand-receptor structure (preferably one that is validated). The computerized scoring analysis includes determining whether the receptor includes one or more hydration sites occupied by localized water, and, if so, assessing a penalty if docking the ligand into the receptor results in unfavorable interaction of the ligand with a localized water molecule remaining at the receptor hydration site (i.e. after docking).
-
Citations
16 Claims
-
1. A method of scoring binding affinity of a proposed ligand molecule for a receptor molecule using a sufficiently programmed computer for the following steps:
-
a. obtaining computer stored data representing a predicted ligand-receptor structure, b. determining whether the receptor alone, without a docked ligand, includes one or more hydration sites occupied by localized water, and, if so, c. determining if after docking a receptor-localized water interacts with a hydrophobic ligand atom, and if the docking of the ligand into the receptor results in unfavorable interaction of the ligand with a localized water molecule occupying a receptor hydration site, d. determining whether one or more of the exceptions conditions i.-iv. is present; i. the hydrophobic ligand atom has a net positively charged ligand atom positioned a distance of 4 atoms or fewer from the hydrophobic ligand atom, where the distance is determined by bond connectivity of the atoms in the ligand; ii. the hydrophobic ligand atom that is part of a ligand —
CH3 group, or a ligand atom within 3 atoms of a —
CH3 group, where the localized water borders the edge of a hydrophobic pocket giving it access to surrounding water;iii. the localized receptor water is positioned within 5 Å
of a positively charged ligand atom;iv. the localized receptor water has hydrogen bonds to the ligand; e. applying a penalty to scoring function of binding affinity if
1) the localized receptor water interacts with a hydrophobic ligand atom as determined in step c, and
2) none of the exception conditions i. iv. is present. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
-
Specification