US2011213558A1PendingUtilityA1
Method for predicting activation energy using an atomic fingerprint descriptor or an atomic descriptor
Assignee: BIOINFORMATICS & MOLECULAR DESIGN RES CTPriority: Nov 12, 2008Filed: Nov 12, 2009Published: Sep 1, 2011
Est. expiryNov 12, 2028(~2.3 yrs left)· nominal 20-yr term from priority
Inventors:Ky Youb NamKyoung Tai NoDoo Nam KimWon Seok OhSung Kwang LeeJi-Hoon JungKwang Hwi ChoChang Joon Lee
G16C 20/30G16C 20/90G16C 20/10G16C 20/50
45
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Claims
Abstract
The present invention provides a method for constructing a database of atomic fingerprint descriptors. The invention provides a method for predicting activation energy using an atomic fingerprint descriptor and an atomic descriptor, the method comprising the steps of: (i) calculating the atomic fingerprint descriptor of a substrate; (ii) comparing the calculated atomic fingerprint descriptor with the constructed atomic fingerprint descriptor database to select an atomic position where cytochrome P450-mediated metabolism occurs; and (iii) predicting activation energy for the selected atomic position using an atomic descriptor. Also, the invention provides a method of predicting the activation energy of CYP450-mediated phase I metabolism using effective atomic descriptors. Specifically, the invention provides a method of predicting the activation energy either for cytochrome P450-mediated hydrogen abstraction or for tetrahedral intermediate formation in cytochrome P450-aromatic hydroxylation using equations including effective atomic descriptors. The method of the invention can rapidly predict activation energy for phase I metabolites at a practical level without having to perform a docking experiment between any additional CYP450 and the substrate, or a quantum mechanical calculation, thereby making it easier to develop new drugs using a computer. Also, the present invention may propose a strategy for increasing the bioavailability of drugs through the avoidance of metabolites based on the possibility of drug metabolism. Furthermore, the method of the present invention proposes new empirical approaches which can also be easily applied to activation energies for various chemical reactions, and makes it possible to explain physical and chemical factors that determine activation energy. In addition, through the prediction of activation energy according to the present invention, it is possible to predict i) metabolic products, ii) the relative rate of metabolism, iii) metabolic regioselectivity, iv) metabolic inhibition, v) drug-drug interactions, and vi) the toxicity of a metabolite.
Claims
exact text as granted — not AI-modified1 . A method for constructing a database of atomic fingerprint descriptors, the method comprising the steps of:
(i) calculating the atomic fingerprint descriptor of a substrate, which is represented by the following equation 1; (ii) predicting activation energy for an atomic position using an atomic descriptor; (iii) predicting cytochrome P450-mediated metabolism using the predicted activation energy; and (iv) comparing the predicted metabolism with experimental metabolism and storing whether the metabolism occurs:
X abc [Equation 1]
wherein X is the chemical symbol of an atom; a is a bond indicator that indicates the number of atoms bonded; b is a ring indicator that indicates whether the atom is part of a ring; and c is an aromatic indicator that indicates whether the atom is an aromatic atom.
2 . The method of claim 1 , wherein the metabolism in step (iii) is aliphatic hydroxylation or aromatic hydroxylation.
3 . The method of claim 1 , wherein the metabolism in step (iii) is N-dealkylation, C-hydroxylation, N-oxidation or O-dealkylation.
4 . The method of claim 1 , wherein the cytochrome P450 enzyme is any one selected from the group consisting of CYP2E1, CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP1A1, CYP1A2, CYP2C19, CYP2D6, CYP1B1, and CYP2A6.
5 . A method for predicting activation energy using an atomic fingerprint descriptor and an atomic descriptor, the method comprising the steps of:
(i) calculating the atomic fingerprint descriptor of a substrate, which is represented by the following equation 1; IS (ii) comparing the calculated atomic fingerprint descriptor with the data, constructed by the method of any one of claims 1 to 4 , to select an atomic position where cytochrome P450-mediated metabolism can occur; and (iii) predicting activation energy for the selected atomic position using an atomic descriptor:
X abc [Equation 1]
wherein X is the chemical symbol of an atom; a is a bond indicator that indicates the number of atoms bonded; b is a ring indicator that indicates whether the atom is part of a ring; and c is an aromatic indicator that indicates whether the atom is an aromatic atom.
6 . The method of claim 5 , wherein the metabolism in step (ii) is aliphatic hydroxylation or aromatic hydroxylation.
7 . The method of claim 5 , wherein the metabolism in step (ii) is N-dealkylation, C-hydroxylation, N-oxidation or O-dealkylation.
8 . The method of claim 5 , wherein the cytochrome P450 enzyme is any one selected from the group consisting of CYP2E1, CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP1A1, CYP1A2, CYP2C19, CYP2D6, CYP1B1, and CYP2A6.
9 . The method of claim 5 , wherein step (iii) comprises predicting the activation energy for cytochrome P450-mediated hydrogen abstraction from a substrate of the following formula 1 using the atomic descriptors [δ het ], [max(δ heavy )], [μ C—H ] and
[
∑
i
R
.
C
.
α
i
]
:
wherein the circle together with Fe—O indicates an oxyferryl intermediate; [δ het ] indicates the net atomic charge of a heteroatom in the alpha-position relative to the reaction center; [max(δ heavy )] indicates the highest atomic charge in X 1 , X 2 and X 3 which are neither hydrogen nor helium; [μ C—H ] indicates the bond dipole of the carbon-hydrogen bond; and
[
∑
i
R
.
C
.
α
i
]
indicates the sum of the atomic polarizabilities of H, C, X 1 , X 2 and X 3 .
10 . The method of claim 9 , wherein the activation energy is predicted according to the following equation:
E a Habs — (B) =25.94+1.88*[δ het ]+1.03*[max(δ heavy )]
wherein E a Habs — (B) indicates activation energy required for abstraction of hydrogen attached to a carbon atom having a heteroatom in the alpha-position relative to the reaction center.
11 . The method of claim 9 , wherein the activation energy is predicted according to the following equation:
E
a
Habs_
(
A
)
=
28.50
-
2.22
*
[
μ
C
-
H
]
+
1.12
*
[
∑
i
R
.
C
.
α
i
]
wherein E a Habs — (A) indicates activation energy required for abstraction of hydrogen attached to a carbon atom having no heteroatom in the alpha-position relative to the reaction center.
12 . The method of claim 5 , wherein step (iii) comprises predicting the activation energy for tetrahedral intermediate formation in cytochrome P450-mediated aromatic hydroxylation for a substrate of the following formula using the atomic descriptors [δ H ] and [mean(α alpha )]:
wherein the circle together with Fe—O indicates an oxyferryl intermediate; [δ H ] indicates the net atomic charge of the hydrogen of the substrate; and [mean(α alpha )] indicates the mean value of the polarizabilities of adjacent carbon atoms.
13 . The method of claim 12 , wherein the activation energy is predicted according to the following equations:
E a aro — o,p =21.34−0.75*[δ H ]−1.24*[(mean(α alpha )]
wherein E a aro — o,p indicates the activation energy for tetrahedral intermediate formation in a benzene having one substituent in the ortho/para-position.
14 . The method of claim 12 , wherein the activation energy is predicted according to the following equations:
E a aro — m =22.14−0.68*[δ H ]−0.83*[mean(α alpha )] wherein E a aro — m indicates the activation energy for tetrahedral intermediate formation in a benzene having one substituent in the meta-position.
15 . The method of claim 12 , wherein the activation energy is predicted according to the following equations:
E a aro — 0,2,3 =21.02−1.49*[δ H ]−0.92*[mean(α alpha )]
wherein E a aro — 0,2,3 indicates the activation energy for tetrahedral intermediate formation in a benzene having 0, 2 or 3 substituents.
16 . A method for predicting a metabolite using the activated energy predicted by the method of claim 5 .
17 . The method of claim 16 , wherein an atomic position having the lowest activation energy is predicted as a position where metabolism occurs.
18 . A method of predicting a drug-drug interaction through the activation energy predicted by the method of claim 5 .
19 . A method of predicting the activation energy for cytochrome P450-mediated hydrogen abstraction from a substrate of the following formula using the atomic descriptors [δ het ], [max (δ heavy )], [μ C—H ] and
[
∑
i
R
.
C
.
α
i
]
:
wherein the circle together with Fe—O indicates an oxyferryl intermediate; [δ het ] indicates the net atomic charge of a heteroatom in the alpha-position relative to the reaction center; [max(δ heavy )] indicates the highest atomic charge in X 1 , X 2 and X 3 which are neither hydrogen nor helium; [μ C—H ] indicates the bond dipole of the carbon-hydrogen bond; and
[
∑
i
R
.
C
.
α
i
]
indicates the sum of the atomic polarizabilities of the atoms H, C, X 1 , X 2 and X 3 .
20 . The method of claim 19 , wherein the cytochrome P450 enzyme is any one selected from the group consisting of CYP2E1, CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP1A1, CYP1A2, CYP2C19, CYP2D6, CYP1B1, and CYP2A6.
21 . The method of claim 19 , wherein, if the C atom of any C—H bond to a target molecule is aliphatic carbon, it is determined to be a position where hydrogen abstraction can Occur.
22 . The method of claim 19 , wherein, if there is a heteroatom in the alpha-position relative to the reaction center, the atomic descriptors [δ het ] and [max (δ heavy )] are calculated.
23 . The method of claim 19 , wherein, if there is no heteroatom in the alpha-position relative to the reaction center, the atomic descriptors [μ C—H ] and
[
∑
i
R
.
C
.
α
i
]
are calculated.
24 . The method of claim 22 , wherein the activation energy is predicted according to the following equation:
E a Habs — (B) =25.94+1.88*[δ het ]+1.03*[max(δ heavy)]
wherein E a Habs — (B) indicates activation energy required for abstraction of hydrogen attached to a carbon atom having a heteroatom in the alpha-position relative to the reaction center.
25 . The method of claim 23 , wherein the activation energy is predicted according to the following equation:
E
a
Habs_
(
A
)
=
28.50
-
2.22
*
[
μ
C
-
H
]
+
1.12
*
[
∑
i
R
.
C
.
α
i
]
wherein E a Habs — (A) indicates activation energy required for abstraction of hydrogen attached to a carbon atom having no heteroatom in the alpha-position relative to the reaction center.
26 . A method of predicting the relative rate of metabolism (k) according to the following Arrhenius equation using the activation energy predicted by the method of any one of claims 19 to 25 :
k=Ae −E a /RT
wherein k is a reaction rate constant, A is a frequency factor, E a is activation energy, R is a gas constant, and T is absolute temperature.
27 . A method of predicting metabolic regioselectivity using the activation energy predicted by the method of any one of claims 19 to 25 .
28 . The method of claim 27 , wherein the metabolic regioselectivity is predicted by predicting the relative rate of metabolism according to the Arrhenius equation using the predicted activation energy and substituting the predicted relative rate of metabolism into the following equation:
P
1
P
2
=
[
ES
1
]
[
ES
2
]
k
5
k
6
wherein P indicates the relative probability of formation of any metabolite of all possible metabolites of a substrate, E is an enzyme, S is a substrate, ES is an enzyme-substrate complex, [ES] is the concentration of the enzyme-substrate complex, and k is reaction rate constant.
29 . A method of predicting the inhibition of metabolism using the activation energy predicted by the method of any one of claims 19 to 25 .
30 . A method of predicting a drug-drug interaction using the activation energy predicted by the method of any one of claims 19 to 25 .
31 . A method of predicting the activation energy for tetrahedral intermediate formation in cytochrome P450-mediated aromatic hydroxylation for a substrate of the following formula using the atomic descriptors [δ H ] and [mean (α alpha )]:
wherein the circle together with Fe—O indicates an oxyferryl intermediate; [δ H ] indicates the net atomic charge of the hydrogen of the substrate; and [mean(α alpha )] indicates the mean values of polarizabilities of adjacent carbon atoms.
32 . The method of claim 31 , wherein the cytochrome P450 enzyme is any one selected from the group consisting of CYP2E1, CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP1A1, CYP1A2, CYP2C19, CYP2D6, CYP1B1, and CYP2A6.
33 . The method of claim 31 , wherein, if the C atom of any C—H bond to a target molecule is aliphatic carbon, it is determined to be a position where hydrogen abstraction occurs.
34 . The method of claim 31 , wherein the atomic descriptors [δ H ] and [mean(α alpha )] are calculated.
35 . The method of claim 34 , wherein the activation energy is predicted according to the following equation:
E a aro — o,p =21.34−0.75*[δ H ]−1.24*[mean(α alpha ]
wherein E a aro — o,p indicates the activation energy for tetrahedral intermediate formation in a benzene having one substituent in the ortho/para-position.
36 . The method of claim 34 , wherein the activation energy is predicted according to the following equation:
E a aro — m =22.14−0.68*[δ H ]−0.83*[mean(α alpha )]
wherein E a aro — m indicates the activation energy for tetrahedral intermediate formation in a benzene having one substituent in the meta-position.
37 . The method of claim 34 , wherein the activation energy is predicted according to the following equation:
E a aro — 0,2,3 =21.02−1.49*[δ H ]−0.92*[mean(α alpha)]
wherein E a aro — 0,2,3 indicates the activation energy for tetrahedral intermediate formation in a benzene having 0, 2 or 3 substituents.
38 . A method of predicting the relative rate of metabolism (k) according to the following Arrhenius equation using the activation energy predicted by the method of any one of claims 31 to 37 :
k=Ae −E a /RT
wherein k is a reaction rate constant, A is a frequency factor, E a is activation energy, R is a gas constant, and T is absolute temperature.
39 . A method of inhibiting metabolic regioselectivity using the activation energy predicted by the method of any one of claims 31 to 37 .
40 . The method of claim 39 , wherein the metabolic regioselectivity is predicted by predicting the relative rate of metabolism according to the Arrhenius equation using the predicted activation energy and substituting the predicted relative rate of metabolism into the following equation:
P
1
P
2
=
[
ES
1
]
[
ES
2
]
k
5
k
6
wherein P indicates the relative probability of formation of any metabolite of all possible metabolites of a substrate, E is an enzyme, S is a substrate, ES is an enzyme-substrate complex, [ES] is the concentration of the enzyme-substrate complex, and k is a reaction rate constant.
41 . A method of predicting metabolic inhibition using the activation energy predicted by the method of any one of claims 31 to 37 .
42 . A method of predicting a drug-drug interaction using the activation energy predicted by the method of any one of claims 31 to 37 .Join the waitlist — get patent alerts
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