Pharmacophore models for the identification of the CYP2D6 inhibitory potency of selective serotonin reuptake inhibitors
First Claim
1. A method of generating a pharmacophore model for the CYP2D6 inhibitory potency of selective serotonin reuptake inhibitor compounds comprising the steps of (i) generating a set of three-dimensional conformers for each of the compounds in a training set comprising five or more selective serotonin reuptake inhibitor compounds;
- (ii) correlating each of the compounds of said training set with an observed value for CYP2D6 inhibitory potency;
(iii) generating from the conformers of step (i) a set of one or more pharmacophore test models, each said pharmacophore test model comprising three or more of the CYP2D6 enzyme active site features selected from the group consisting of the hydrogen bond donor feature, the hydrogen bond acceptor feature, the hydrophobic region feature, the ionizable region feature and the ring aromatic feature, arranged in three-dimensional space;
(iv) calculating the CYP2D6 inhibitory potency for each conformer generated in step (i) towards each of the pharmacophore test models generated in step (iii);
(v) calculating the total cost for each pharmacophore test model; and
(vi) choosing the lowest cost pharmacophore test model as the pharmacophore model.
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Abstract
The present invention relates to novel screening methods which enable the selection of selective serotonin reuptake inhibitor (SSRI) compounds which do not possess significant inhibitory potency towards cytochrome P450 enzymes, in particular, CYP2D6. The present invention also relates to a method of generating a pharmacophore model for the CYP2D6 inhibitory activity of SSRI compounds; to methods for the discovery of molecules that are potential SSRI compounds which do not possess significant inhibitory potency towards the CYP2D6 enzyme; to methods of modeling the features of the CYP2D6 pharmacophore useful in selecting SSRI'"'"'s which do not possess significant potency towards CYP2D6. Further, the invention also relates to pharmaceutical compositions comprising an SSRI compound which does not possess significant potency towards the CYP2D6 enzyme identified by methods of the invention; to the uses of an SSRI compound identified by the methods of the invention for the manufacture of medicaments and for the treatment of a condition, a disorder or a disease in a mammal for which an SSRI compound identified by the method of the invention is therapeutically useful.
119 Citations
43 Claims
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1. A method of generating a pharmacophore model for the CYP2D6 inhibitory potency of selective serotonin reuptake inhibitor compounds comprising the steps of
(i) generating a set of three-dimensional conformers for each of the compounds in a training set comprising five or more selective serotonin reuptake inhibitor compounds; -
(ii) correlating each of the compounds of said training set with an observed value for CYP2D6 inhibitory potency;
(iii) generating from the conformers of step (i) a set of one or more pharmacophore test models, each said pharmacophore test model comprising three or more of the CYP2D6 enzyme active site features selected from the group consisting of the hydrogen bond donor feature, the hydrogen bond acceptor feature, the hydrophobic region feature, the ionizable region feature and the ring aromatic feature, arranged in three-dimensional space;
(iv) calculating the CYP2D6 inhibitory potency for each conformer generated in step (i) towards each of the pharmacophore test models generated in step (iii);
(v) calculating the total cost for each pharmacophore test model; and
(vi) choosing the lowest cost pharmacophore test model as the pharmacophore model. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 23, 25, 26, 39, 40, 43)
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16. A method of generating a pharmacophore model for the CYP2D6 inhibitory potency of selective serotonin reuptake inhibitor compounds comprising the steps of
(i) correlating the chemical features of the conformers of the compounds in a training set of selective serotonin reuptake inhibitor compounds with a set of two- and/or three-dimensional descriptors for the active site of the CYP2D6 enzyme; - and
(ii) generating an equation relating the observed CYP2D6 inhibitory potency of said selective serotonin reuptake inhibitor compounds to a set of generated two- and/or three dimensional descriptors for the selective serotonin reuptake inhibitor compound. - View Dependent Claims (17, 18, 19, 24, 27, 28, 29, 30, 31, 32, 33, 41, 42)
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20. A method for determining the CYP2D6 inhibitory potency of an selective serotonin reuptake inhibitor compound comprising the steps of
(i) generating the two- and/or three-dimensional descriptors for said selective serotonin reuptake inhibitor compound; -
(ii) inputting said three-dimensional descriptors into an equation relating the observed CYP2D6 inhibitory activity of a set of selective serotonin reuptake inhibitor compounds to a set of three-dimensional descriptors generated for those selective serotonin reuptake inhibitor compounds; and
(iii) solving said equation for the CYP2D6 inhibitory activity of the selective serotonin reuptake inhibitor compound corresponding to the generated three-dimensional descriptors of step (i). - View Dependent Claims (21, 22)
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34. A method of designing de novo compounds that are selective serotonin reuptake inhibitor compounds which do not possess significant inhibitory potency towards CYP2D6 comprising the step of
(i) correlating the three-dimensional descriptors for a pharmacophore model for selective serotonin reuptake inhibitor compounds that possess inhibitory potency towards CYP2D6 with randomly generated molecules having chemical features corresponding to said descriptors; - and
(ii) choosing a generated molecule with a CYP2D6 K1 (apparent) value of 1 μ
M or greater. - View Dependent Claims (35, 36, 37)
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38. A method of designing de novo compounds that are selective serotonin reuptake inhibitor compounds which possess an inhibitory potency towards CYP2D6 corresponding to an K1 (apparent) value of greater than 10 μ
- M comprising the steps of
(i) generating a three-dimensional descriptor for a pharmacophore model for selective serotonin reuptake inhibitor compounds which possess an inhibitory potency towards CYP2D6 corresponding to an K1 (apparent) value of 10 μ
M or greater; and
(ii) correlating said descriptors of step (i) with compounds having chemical features corresponding to said descriptors.
- M comprising the steps of
Specification