Rapid computational identification of targets
OwnerAdrian Elcock, William Rockeyinventors
Life of this patent
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Abstract
Disclosed are compositions and methods for rapid computational identification of targets.
Claims44
A method of identifying a target for a molecule comprising the steps:
- a) modeling the molecule in complex with a known target for the molecule, b) obtaining potential target molecules by selecting potential target molecules with a defined homology to the known target, c) determining the binding affinity of a potential target with the molecule by modeling the potential target with the molecule, wherein side chain rotamers are sampled from a rotamer library during homology modeling.
A method of identifying a target for a molecule comprising the steps:
- a) obtaining a structural model of the molecule and a known target, wherein the known target comprises a known target-molecule binding domain, b) obtaining a potential target by identifying potential targets having a defined homology with the known target, c) performing homology modeling with the identified potential target, wherein during the homology modeling backbone conformations are held identical to the known target, wherein sidechains are sampled from a library of rotamers, and d) calculating a binding energy of the molecule and the identified potential target.
A method of identifying a desired protein-molecule interaction comprising:
- (a) determining structural information for a protein known to interact with the molecule of interest;
- (b) identifying which residues of the protein of step a) interact with the molecule;
- (c) comparing the residues identified in step b) with a database of proteins;
- (d) selecting proteins having an area of similarity to the residues identified in step b);
- (e) calculating interaction energies between the proteins of step d) and the molecule of interest;
- and (f) determining which proteins are capable of interacting in a desired fashion with the molecule of interest.
A computer system having a processing means, memory means, and a visual display means, the memory means containing sequence information for a protein known to interact with a molecule of interest, and modules containing information to be compared with the sequence information of the protein known to interact with the molecule of interest, and the processing means being operable to compute molecule-protein binding energy using the method of claim 52.
A method of making a pharmaceutical comprising a) modeling the pharmaceutical in complex with a known target for the molecule;
- b) obtaining potential target molecules by selecting potential target molecules with a defined homology to the known target, c) determining the binding affinity of a potential target with the pharmaceutical by modeling the potential target with the pharmaceutical, wherein a Monte Carlo function is used for sampling of side chain rotamers during homology modeling;
- d) identifying target molecules of the pharmaceutical;
- e) synthesizing the pharmaceutical;
- and f) testing the pharmaceutical for binding to the target molecule.
A method of inhibiting a receptor selected from the group consisting of CRK7, SYK, TEC, RET, BMX, ABL, IKKb, TRKA, HER4/ErbB, SgK288, DDR2, TRKB, ARG, TRKC, DDR1, TIE1, FMS, YES, ACK, FGFR2, BLK, FRK, FYN, CSK, ANKRD3, HCK, MST1, SRC, LYN, IKKa, FGR, TXK, NDR2, FLT1, LCK, NDR1, PDGFRa, PDGFRb, FLT4, MST2, and KIT comprising incubating the receptor with the drug imatinib.
A method of inhibiting a receptor selected from the group consisting of MUSK, FLT3, CDK2, DYRK1A, FLT4, CDK3, CDC2, KDR, CDKL1, TRKB, CASK, MAK, TRKC, DYRK1B, CDK5, ROR1, PCTAIRE2, TRKA, PCTAIRE1, FLT1, TIE1, RET, CDK7, CDKL3, PDGFRa, ROR2, JAK2, AurA, FGFR2, PCTAIRE3, CDC7, CDKL2, AurC, AurB, GCN2, TLK2, TLK1, CDK9, TIE2, MAP3K4, KIT, MSK1, and PLK2 comprising incubating the receptor with the drug purvanol.
A method of inhibiting a receptor selected from the group consisting of FRK, DDR1, BRK, QIK, EphA1, EphB2, DDR2, QSK, EphB3, SRM, EphB1, ACK, EphA6, SIK, MOK, YANK2, EphB4, EphA8, HER4/erbB4, RET, YANK1, YANK3, EphA4, EphA5, GAK, EDFR, PDGFRa, PDGFRb, EphA2, FGR, RIPK3, YES, MLK4, EphA3, LCK, HER2/ErbB2, SRC, BLK, BTK, FYN, LYN, HCK, RIPK2, CSK, ARG, TXK, Domain2_RSK4, p38α, p38β, and CaMKK1 comprising incubating the receptor with the drug SB 203580.
A method of displaying a representation of a protein-molecule interaction on a computer having a processing means, a memory means, an input means and an output means comprising:
- receiving the three-dimensional coordinates of atoms of the protein;
- producing a representation of the protein based upon the received coordinates;
- and displaying the representation of the protein-molecule interaction on the visual display means, wherein the protein in the protein-molecule interaction comprises a protein which is a homologue of the native target of the molecule.
An apparatus comprising:
- (a) a system data store capable of storing coordinate sets;
- and
- (b) a system processor in communication with the system data store that carries out the following steps:
- (i) modeling a molecule in complex with a known target for the molecule,
- (ii) obtaining potential target molecules by selecting potential target molecules with a defined homology to the known target,
- (iii) determining the binding affinity of a potential target with the molecule by modeling the potential target with the molecule,
- wherein a Monte Carlo function is used for sampling of side chain rotamers during homology modeling.
Dependencies are inferred from the claim text.