417
12 Consensus Drug Design Using IT Microcosm
Thus, it was established computationally and confirmed experimentally that the
antiarrhythmic activity of the clathrates of compound (XIV) with glycyrrhizinic
acid equaled the activity of the pure compound (XIV).
The results obtained show that IT Microcosm makes it possible to predict the
pharmacological activity of supramolecular complexes and to optimize their composition.
12.5.3 Mixtures of Natural and Synthetic Organic Compounds
Combination drugs that include several active substances are used widely in clinical practice. Such drugs show effects of interaction between pharmacologically active compounds, including the synergistic effect that is of the greatest interest for
practical purposes. The difference between mixtures of compounds and molecular
complexes is more or less relative; it is determined by the energy of the intermolecular interactions; it is believed that mixtures show a prevalence of weak-dispersion
interactions, whereas more energetically stable bonds, such as ion-dipole bonds
and hydrogen bonds that are due to charge transfer, are more typical of molecular
complexes [85]. We defined a substance as a mixture if it consisted of two or more
individual substances and if it is not possible make any reasonable assumptions
about the type of the molecular interactions between them. The prediction of the
biological activity of mixtures has been successfully performed using the software
HIT QSAR [50], PASS [52], ISIDA [66] and CORAL [90].
Several examples are given below of using IT Microcosm successfully in the
prediction of the pharmacological activity of mixtures; these examples include predictions accounting for the synergism of the components [35, 74, 75, 97, 105, 111,
112, 114, 119, 120].
12.5.3.1 Spectrum of the Pharmacological Activity of Juglans Regia Extract
Juglans regia extracted from fruits of milky-wax ripeness is a veterinary drug [35].
It consists of 23 main active substances: juglone (CAS 481-39-0), leucoanthocyan
(2-phenylchromen-2-ol), inosite (CAS 6917-35-7), β-sitosterol (CAS 83-46-5) and
chlorophyll A (CAS 479-61-8); gallic (CAS 149-91-7), ellagic (CAS 476-66-4),
palmitic (CAS 57-10-3), stearic (CAS 57-11-4), lauric (CAS 143-07-7), myristic
(CAS 544-63-8), arachidic (CAS 506-30-9), linolenic (CAS 463-40-1), linoleic
(CAS 60-33-3), oleic (CAS 112-80-1) and palmitoleic (CAS 2091-29-4) acids; and
vitamins A (CAS 68-26-8), B 12 (CAS 68-19-9), C (CAS 50-81-7), D (CAS 67-970), E (CAS 10191-41-0), P (CAS 153-18-4) and PP (CAS 98-92-0).
For each one of these 23 compounds, estimates of the presence of 13 types of
pharmacological activity were calculated using decision rules developed by IT Microcosm on training sets with known drug substances (see Sect. 3).
12 Consensus Drug Design Using IT Microcosm
Thus, it was established computationally and confirmed experimentally that the
antiarrhythmic activity of the clathrates of compound (XIV) with glycyrrhizinic
acid equaled the activity of the pure compound (XIV).
The results obtained show that IT Microcosm makes it possible to predict the
pharmacological activity of supramolecular complexes and to optimize their composition.
12.5.3 Mixtures of Natural and Synthetic Organic Compounds
Combination drugs that include several active substances are used widely in clinical practice. Such drugs show effects of interaction between pharmacologically active compounds, including the synergistic effect that is of the greatest interest for
practical purposes. The difference between mixtures of compounds and molecular
complexes is more or less relative; it is determined by the energy of the intermolecular interactions; it is believed that mixtures show a prevalence of weak-dispersion
interactions, whereas more energetically stable bonds, such as ion-dipole bonds
and hydrogen bonds that are due to charge transfer, are more typical of molecular
complexes [85]. We defined a substance as a mixture if it consisted of two or more
individual substances and if it is not possible make any reasonable assumptions
about the type of the molecular interactions between them. The prediction of the
biological activity of mixtures has been successfully performed using the software
HIT QSAR [50], PASS [52], ISIDA [66] and CORAL [90].
Several examples are given below of using IT Microcosm successfully in the
prediction of the pharmacological activity of mixtures; these examples include predictions accounting for the synergism of the components [35, 74, 75, 97, 105, 111,
112, 114, 119, 120].
12.5.3.1 Spectrum of the Pharmacological Activity of Juglans Regia Extract
Juglans regia extracted from fruits of milky-wax ripeness is a veterinary drug [35].
It consists of 23 main active substances: juglone (CAS 481-39-0), leucoanthocyan
(2-phenylchromen-2-ol), inosite (CAS 6917-35-7), β-sitosterol (CAS 83-46-5) and
chlorophyll A (CAS 479-61-8); gallic (CAS 149-91-7), ellagic (CAS 476-66-4),
palmitic (CAS 57-10-3), stearic (CAS 57-11-4), lauric (CAS 143-07-7), myristic
(CAS 544-63-8), arachidic (CAS 506-30-9), linolenic (CAS 463-40-1), linoleic
(CAS 60-33-3), oleic (CAS 112-80-1) and palmitoleic (CAS 2091-29-4) acids; and
vitamins A (CAS 68-26-8), B 12 (CAS 68-19-9), C (CAS 50-81-7), D (CAS 67-970), E (CAS 10191-41-0), P (CAS 153-18-4) and PP (CAS 98-92-0).
For each one of these 23 compounds, estimates of the presence of 13 types of
pharmacological activity were calculated using decision rules developed by IT Microcosm on training sets with known drug substances (see Sect. 3).