Patent NZ-603495-A (NZ)
Title: Algorithm for designing irreversible inhibitors
Inventor: SINGH JUSWINDER
IPC: G16B15/00
Filed: 2009-09-04
Abstract: NZ 603495 Disclosed is a method for generating an inhibitor that covalently binds a target polypeptide, comprising: providing a structural model of a reversible inhibitor bound to a binding site in a target polypeptide, wherein the reversible inhibitor makes non-covalent contacts with the binding site; identifying a Cys residue in the binding site of the target polypeptide that is adjacent to the reversible inhibitor when the reversible inhibitor is bound to the binding site; providing at least one structural model of a warhead group, the warhead comprising a reactive chemical functionality capable of reacting with the Cys residue and forming a covalent bond between the sulphur atom of the Cys residue in the binding site and the reactive chemical functionality of the warhead group; identifying a substitutable position of the reversible inhibitor to which the warhead group can be bonded, optionally through a linker, such that the bond formed between the sulphur atom of the Cys residue in the binding site and the reactive chemical functionality of the warhead group has a bond length of less than about 2Å; bonding the warhead group, optionally through the linker, to the substitutable position of the reversible inhibitor thereby identifying a candidate inhibitor, in which steps a) to e) are performed in silico; and producing the candidate inhibitor that covalently binds a target polypeptide by synthesising a compound which has the chemical structure of the candidate inhibitor identified in step e), wherein the steps of synthesising the compound comprise: combining an intermediate comprising a portion of the structure of the candidate inhibitor with a reactive intermediate comprising the warhead or a portion thereof via a bond forming reaction; and wherein the warhead has the formula -X-L-Y, wherein X is a bond or a bivalent C1-C6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by -NR-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, -C(=NR)-, -N=N-, or –C(=N2)-; L is a covalent bond or a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, -NR-, -N(R)C(O)-, -C(O)N(R)-, -N(R)SO2-, -SO2N(R)-, -O-, -C(O)-, -OC(O)-, -OC(O)-, -C(O)O-, -S-, -SO-, -SO2-, -C(=S)-, -C(=NR)-, -N=N-, or -C(=N2)-; Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulphur, and wherein said ring is substituted with 1-4 groups independently selected from -Q-Z, oxo, NO2, halogen, CN, or C1-6 aliphatic, wherein: Q is a covalent bond or a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -C(O)-, -SO-, or -SO2-; and Z is a hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, or CN; each R group is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulphur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulphur wherein the warhead comprises a reactive functional group capable of forming a covalent bond with the sulfhydryl group of cysteine.