415
12 Consensus Drug Design Using IT Microcosm
IT Microcosm performed an optimization of the composition of supramolecular
clathrate complexes of glycyrrhizinic acid (XII) with two pharmacons: an antioxidant agent (XIII) [5] and an antiarrhythmic agent (XIV) [78] (Fig. 12.6) with the
purpose of achieving the maximal pharmacologic effect.
A prediction of the activity of pure pharmacons and pharmacon clathrates with
glycyrrhizinic acid with molar compositions of 1:1, 1:2, 1:3 and 1:4 was performed
in the normal and risk strategies using training sets for the antioxidant and antiarrhythmic activity of condensed azole derivatives (see Sect. 3 and 4). The values of
the membership functions for the classes of active and highly active compounds, as
well the ranks of these values in ascending order, served as a metric of the expected
activity. The conservative strategy was not employed due to the nonstandard structures of the predicted compounds.
The predicted results for the antioxidant activities of the compound (XIII) clathrates with glycyrrhizinic acid are shown in Table 12.16.
According to the sum of the rank estimates ∑∑Rank, the antioxidant activity of
all compound (XIII) clathrates should exceed the activity of the pure nonclathrated
compound (XIII). In this case, the comparable value of the antioxidant activity should
decrease in the series: (XIII–GA 1:4) > (XIII–GA 1:3) > (XIII–GA 1:2) ≈ (XIII–GA
1:1) > (XIII). The clathrate (XIII–GA 1:4) should show the highest activity. The (XIII–
GA 1:2) and (XIII–GA 1:1) complexes should show the lowest activities.
Experimentally, the substances were studied in vivo on rats at a dose equivalent
to 10 mg/kg of the pharmacon per os. The total antioxidant activity of the blood
plasma was assessed by a method based on the ability of the biological agents to
inhibit the accumulation of lipid peroxidation products in a suspension of egg-yolk
lipoproteins [44]. Δ max , the maximum percentage of the lipid-peroxidation inhibition (in relation to the outcome) observed for nine hours of the experiment, served
as an index of the antioxidant activity.
Table 12.16 Prediction of the antioxidant activity of the clathrate complexes of compound (XIII)
with glycyrrhizinic acid
Composition
Fb Norm
a
Fb Risk
b
Rank Norm
c
Rank Risk
d
∑Rank
e
Presence of the activity
XIII
0.9999
0.5906
3
1
4
XIII–GA 1:1
0.9999
0.5932
3
2
5
XIII–GA 1:2
0.9999
0.5945
3
3
6
XIII–GA 1:3
0.9999
0.5950
3
4
7
XIII–GA 1:4
0.9999
0.5953
3
5
8
High activity
∑∑Rank
f
XIII
0.0001
0.4349
1
1
2
6
XIII–GA 1:1
0.6116
0.4887
5
2
7
12
XIII–GA 1:2
0.5908
0.4929
3
3
6
12
XIII–GA 1:3
0.5908
0.4949
3
4
7
14
XIII–GA 1:4
0.5908
0.4974
3
5
8
16
a
Membership function for the normal strategy of prediction
b
Membership function for the risk strategy of prediction
c
The Fb Norm values ranked in ascending order
d
The Fb Risk values ranked in ascending order
e
The sum of the ranks in the strategies
f
The sum of the ranks in the strategies and the activity gradations
12 Consensus Drug Design Using IT Microcosm
IT Microcosm performed an optimization of the composition of supramolecular
clathrate complexes of glycyrrhizinic acid (XII) with two pharmacons: an antioxidant agent (XIII) [5] and an antiarrhythmic agent (XIV) [78] (Fig. 12.6) with the
purpose of achieving the maximal pharmacologic effect.
A prediction of the activity of pure pharmacons and pharmacon clathrates with
glycyrrhizinic acid with molar compositions of 1:1, 1:2, 1:3 and 1:4 was performed
in the normal and risk strategies using training sets for the antioxidant and antiarrhythmic activity of condensed azole derivatives (see Sect. 3 and 4). The values of
the membership functions for the classes of active and highly active compounds, as
well the ranks of these values in ascending order, served as a metric of the expected
activity. The conservative strategy was not employed due to the nonstandard structures of the predicted compounds.
The predicted results for the antioxidant activities of the compound (XIII) clathrates with glycyrrhizinic acid are shown in Table 12.16.
According to the sum of the rank estimates ∑∑Rank, the antioxidant activity of
all compound (XIII) clathrates should exceed the activity of the pure nonclathrated
compound (XIII). In this case, the comparable value of the antioxidant activity should
decrease in the series: (XIII–GA 1:4) > (XIII–GA 1:3) > (XIII–GA 1:2) ≈ (XIII–GA
1:1) > (XIII). The clathrate (XIII–GA 1:4) should show the highest activity. The (XIII–
GA 1:2) and (XIII–GA 1:1) complexes should show the lowest activities.
Experimentally, the substances were studied in vivo on rats at a dose equivalent
to 10 mg/kg of the pharmacon per os. The total antioxidant activity of the blood
plasma was assessed by a method based on the ability of the biological agents to
inhibit the accumulation of lipid peroxidation products in a suspension of egg-yolk
lipoproteins [44]. Δ max , the maximum percentage of the lipid-peroxidation inhibition (in relation to the outcome) observed for nine hours of the experiment, served
as an index of the antioxidant activity.
Table 12.16 Prediction of the antioxidant activity of the clathrate complexes of compound (XIII)
with glycyrrhizinic acid
Composition
Fb Norm
a
Fb Risk
b
Rank Norm
c
Rank Risk
d
∑Rank
e
Presence of the activity
XIII
0.9999
0.5906
3
1
4
XIII–GA 1:1
0.9999
0.5932
3
2
5
XIII–GA 1:2
0.9999
0.5945
3
3
6
XIII–GA 1:3
0.9999
0.5950
3
4
7
XIII–GA 1:4
0.9999
0.5953
3
5
8
High activity
∑∑Rank
f
XIII
0.0001
0.4349
1
1
2
6
XIII–GA 1:1
0.6116
0.4887
5
2
7
12
XIII–GA 1:2
0.5908
0.4929
3
3
6
12
XIII–GA 1:3
0.5908
0.4949
3
4
7
14
XIII–GA 1:4
0.5908
0.4974
3
5
8
16
a
Membership function for the normal strategy of prediction
b
Membership function for the risk strategy of prediction
c
The Fb Norm values ranked in ascending order
d
The Fb Risk values ranked in ascending order
e
The sum of the ranks in the strategies
f
The sum of the ranks in the strategies and the activity gradations