Columbia University

Schrodinger, LLC

Shrodinger, LLC

Richard A Friesner

Robert Murphy

Thomas R Young

Bruce J Berne

Robert Abel

John Gunn

Alessandro Monge

A method of scoring binding affinity of a proposed ligand molecule for a receptor molecule using computer analysis and computer data bases to accounts for the increase in energy required where docking disrupts or partially disrupts the &#x3c0;-conjugated character of the ligand when bound to the receptor. The method uses data representing one or more proposed ligand molecules to be scored and data representing the receptor molecule. Computer analysis of the proposed ligand molecule data determines whether the ligand includes at least one &#x3c0;-conjugated moiety having multiple possible geometries, one of those geometries being characterized by less delocalization of electrons across the &#x3c0;-conjugated moiety than the delocalization of electrons characterizing another of those geometries. Computer analysis of the predicted ligand-receptor structure determines whether the ligand in the ligand-receptor structure adopts the geometry characterized by less delocalization. If so, a penalty is explicitly imposed for reduced delocalization of electrons across the &#x3c0;-conjugated moieties.

Binding affinity scoring with penalty for breaking conjugation between aromatic ligand groups

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).

Binding affinity scoring function penalizing compounds which make unfavorable hydrophobic contacts with localized water molecules in the receptor active site

Scoring functions can be markedly improved by taking into account the status environs of ligand rings (or indeed other bulky rigid ligand structures) on the ligand when the ligand is complexed with the receptor. In its most general form, the invention features, quantifying a particular component of binding affinity between a ligand and a receptor molecule. Specifically, the component in question takes into account the spatial relationship between ligand ring structure(s) (or bulky rigid ligand structures) and their ambient surroundings when the ligand is bound to the receptor molecule. The method steps may be used when quantifying a component that reflects these particular ligand features alone, or the steps may be part of a comprehensive method of quantifying binding affinity which includes numerous other factors that relate to binding affinity in addition to the component. For example, one may calculate an initial binding affinity and then adjust the initial binding affinity by a factor obtained at least in part based on the classification of the ring structure.

Binding affinity scoring function including factor for environs of ring or bulky rigid group

A computer-implemented method for calculating a value representative of interaction (VRI) of a proposed ligand with a specified receptor. Hydrophobic interactions between one or more ligand atoms and one or more receptor atoms are scored by a method that awards a bonus for the presence of hydrophobic enclosure of one or more ligand atoms by the receptor. Also, charge-charge hydrogen bonds between a ligand and a receptor are scored by setting a default value for a charge-charge hydrogen bond and awarding a bonus above the default value when one or more specialized predetermined charge-charge hydrogen bond criteria is satisfied. Various charge-charge hydrogen bond criteria are used. Zwitterions, charge, salvation, geometry and electrostatic energy are accounted for.

Predictive scoring function for estimating binding affinity

Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., 'hydration sites'), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.

Methods of calculating differences of binding affinities between congeneric pairs of ligands by way of a displaced solvent functional

The subject invention provides a method for determining the most stable tertiary structure of a protein having a known primary structure which comprises the steps of (a) producing a reduced representation of the protein by assigning to the protein (i) all secondary structural motifs present therein and (ii) all .phi. and .PHI. dihedral angles for the amino acid residues present therein; (b) determining which conformations of the reduced representation are physically permissible, so as to determine which conformations of the protein are physically permissible; and (c) determining which of the physically permissible conformations of the protein possesses the lowest free energy, so as to thereby determine the most stable tertiary structure of the protein.

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New York, NY, United States of America

Richard A Friesner