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3Structure- and ligand-based approaches in drug designing 49
3.7.1 Mean squares
This is obtaine d when the total sum of the squares is corrected for degrees of freedom.
The significanc
e of regression models is evaluated using this term. Its value is used to
calculate the error of measurement in the X data.
3.7.2 Training set
This is a portion of a data set classified or used to fit a model for predicting the values
that ar
e known in the tr
aining set.
3.7.3 Test set
This is a set of data used to assess the utility of a predictive relationship and its
str
gth. It is prepared from the whole data set to evaluate the training set.
en
3.7.4 Advantages of QSAR
1. Quantification of the effect of structure on activity.
2
Help to predict novel analogues for synthesis.
.
3. Interaction between functional groups present in a molecule having greatest
activity with those of their target can be understood.
4. Prediction of biological activity.
3.7.5 Disadvantages of QSAR
1. False correlations may arise because of experimental error in biological data.
2
If the training data set is not large enough, the data collected may reflect the com-
.
plete property space.
3. 3D structures of ligand binding to receptor may not be available.
50 Sumitra Nain*, Garima Mathur, Girish Kumar Gupta, Sarvesh Paliwal
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3.7.6 Application of QSAR
3.7.6.1 Chemical
1. A QSAR application was used to predict boiling points [52]. In organic chemistry,
a stron
g correlation between structure and properties may exist.
2. Hammett equation, Taft equation and pKa prediction methods were developed
[53].
3.7.6.2 Biological
1. The biological activity of the molecules is measured in assays to suggest the level
of inhibition or acti
ation for a particular signal transduction or metabolic path-
v
ways.
2. QSAR has also been used in drug discovery to predict chemical structures having
good inhibitory or agonistic effects on specific targets and low toxicity.
3. Partition coefficient log P is predicted to identify “druglikeness”.
4. QSAR also helps in the study of interactions between the structural domains of
proteins [53].
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52 Sumitra Nain*, Garima Mathur, Girish Kumar Gupta, Sarvesh Paliwal
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
[52] Fraczkiewicz R. 2007. In silico prediction of ionization. Comprehensive medicinal chemistry II.
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Luciana Scotti*, Francisco J. B. Mendonça Júnior, Marcelo S. daSilva,
Marcus T. Scotti
4 Drug design applied to natural products against
neglected diseases
Abstract: Natural products can be defined as those compounds isolated from plants
which provide a variety of lead structures used in the development of new drugs by
the pharmaceutical industry. Interest in these substances has increased because of
their beneficial effects on human health, such as antiviral, anti-allergic, antiplatelet,
anti-inflammatory, antitumor, antioxidant and antiparasitic activities. The Neglected
Diseases are 17 diseases transmitted by virus, protozoa, helminthes, and bacteria,
they are infections principally caused by tropical parasites, affecting mainly people
who live in poor countries, and, having differing symptoms, may often lead to death.
The available therapeutic drugs used to treat these diseases are either obsolete, toxic,
or have questionable efficacy, possibly from encountering bacterial resistance. Discovery of new, safe, effective, and affordable active molecules is urgently needed.
Natural organisms, especially plants, provide innumerable molecules with the potential to treat these diseases. This work introduces general concepts, and discusses the
neglected diseases, reporting on some of the enzymatic targets studied when developing new drugs to treat these ills.
4.1 Natural products
The known organic substances, in general, have all been produced by Nature, yet it
is the kingdom Plantae which has contributed most significantly to the discovery of
useful substances that treat human disease. The development of organic chemistry
(mostly in the 19th century) occurred in parallel with the study of plants. The angiosperms are source plants of many natural products, having an undoubtedly unique
development, as evidenced by the occurrence of their distinct and complex metabolites [1].
Natural products often result from an optimized evolutionary process in which
chemicals have been under the selective forces of coevolution, organisms producing
substances in the presence of their predators. These natural compounds have been
utilized by humans since ancient times to treat and cure their diseases. Traditional
Chinese medicine is the best example of natural products’ efficiency, especially in the
discovery of new active chemical entities. These compounds are present in fruits and
vegetables and are important components of our daily diets. Of the existing plants in
the world, most of which are unknown from a scientific point of view, only about 5%
of the approximately 250–500thousand species have been biologically studied and
54 Luciana Scotti*, Francisco J. B. Mendonça Júnior, Marcelo S. daSilva, Marcus T. Scotti
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
evaluated. Natural products are often phenolic compounds, flavonoids, alkaloids, or
terpenes; secondary plant metabolites that may provide several benefits to our health.
These benefits include cosmetic action, cardio-protective effects, anti-inflammatory
activity, and usefulness in the treatment of cancer and the neglected diseases [2–4].
The use of natural products has been the single most successful strategy for
discovering new medicines, and many medical breakthroughs are based on natural
products. Half of the top 20best-selling drugs are natural chemical compounds, and
their total sales amount to US$ 16billion yearly. These numbers suggest that natural
chemicals may well be considered pre-optimized for bioactive potential, and therefore possess “drug-like properties” [5–7].
New molecules are continually being reported in the literature, many with relevant pharmacological activity, such as taxol, forskolin, and artemisinin, etc. (see
the Fig.4.1). It is important to remember that plants have contributed over the years
to obtaining various widely used drugs, such as morphine, emetine, vincristine, colchicine, and rutin, etc. (Fig.4.1). In the 1980s, consumers in the US paid more than
8billion dollars for prescriptions with active natural products, and about 80% of all
people use natural compounds in the treatment of their diseases [8–11].
Taxo l
H3C
H
C
2
Forskolin
(a)
HO
HN
H3C
O
O
H
C
3
O
O
O
CH
O
OH
CH
OH
O
CH
3
3
3
O
O
O
CH
O
3
O
O
C
H
3
O
CH
CH
3
3
O
O
Artemisinin
O
CH
3
OH
O
H
H
C
3
O
O
C
3
CH
3
H3C
OH
HO
HO
OH
O
N
H
C
3
Morphine
Fig. 4.1: Some natural products.
4Drug design applied to natural products against neglected diseases 55
There are several therapeutically attractive metabolites from marine organisms that
have proven to be effective modulators of biological targets such as phospholipases,
adenosine receptors, and which are useful in tumor models. Examples of these candidates (or structural models) for drugs follow: manoalide (an irreversible inhibitor
of phospholipase A
Prostaglandin A
CH
CH
3
O
Emetine Vincristine
3
O
N
) (Fig.4.2), lufarolide (cytotoxic in human lymphoma cells), and
2
(Fig.4.2) [11–15].
2
H3C
O
O
H3C
O
O
OH
O
N
H3C
HN
CH
CH
3
O
O
CH
3
3
N
O
H
C
3
O
HN
CH
3
O
N
OH
CH
3
OH
HO
O
HO
O
HO
OH
Rutin
(b)
Fig. 4.1: (continued)
O
O
O
OH
O
OH
CH
OH
3
OH
OH
H
O
N
C
H
3
O
O
O
CH
3
O
CH
3
CH
O
3
CH
3
Colchicine
56 Luciana Scotti*, Francisco J. B. Mendonça Júnior, Marcelo S. daSilva, Marcus T. Scotti
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H
C
3
C
H
C
3
H
C
3
H
C
CH
3
CH
C
H
3
OH
3
3
Prostaglandin A
2
O
OH
O
OH
O
O
Manoalide
O
O
O
O
OH
O
Lupharolide
H
3
H
C
3
Fig. 4.2: Marine natural products.
New chemical bioactive entity (bioNCEs) studies done by industrial research laboratories have adopted techniques such as Combinatorial Chemistry to obtain more
compounds. Through this technology, reactions are done in several steps, occurring
in parallel or in mixtures, with few reagents. Products are reagent combinations and
therefore large numbers of new compounds can be generated.
4.2 Medicinal chemistry
Medicinal chemistry, in a modern view, is dedicated to understanding the molecular
mechanism, chemical relationships, and pharmacological activity involved in drug
action through pharmacodynamic and pharmacokinetic factors. The introduction of
new technologies has become a prime concept in medicinal chemistry, expanding
its interdisciplinary character. Most drugs are small bioactive molecules that interact with specific macromolecules or receptors, resulting in their therapeutic effects.
Modern computational methods can determine the different qualitative and quantitative contributions of the structural subunits of different drugs. Pharmacokinetic
and toxicity factors of new drug candidates can be evaluated virtually using modern
computational tools. The computer has become an inseparable ally, allowing computational studies that model the chemistry and molecular dynamics of medicinal
chemistry [16–18].
Using several computational tools, researchers can create new virtual candidate ligands for receptor sites in three dimensions (3D). Pharmaceutical companies
4Drug design applied to natural products against neglected diseases 57
report that spending on research and development in 2004 was about 33billion US
dollars, representing real growth year to year in investment, this does not correspond,
however, to a proportional increase in discoveries of new active molecular candidates
for innovative drugs in the market [19].
Natural products have had an important and decisive role in the development
of modern medicinal chemistry and drug design. It has been observed (during the
last 200years) that the complexity, chemical diversity, and biological properties of
natural products have all aided in the discovery of important new drugs [20]. In the
last 30years, the development of new bioassay techniques, biotech methods, bioguided phytochemical studies, automated high-throughput screening, and high performance analytical methods have introduced both new concepts and possibilities for
rational drug design and drug discovery. With the development of new spectroscopic
techniques, organic chemists have been able to elucidate the complex molecular
structures of natural constituents quickly. As examples: gossypol (Fig.4.3) obtained
from the cotton seed oil (Gossypium sp.) is widely used in China as a male contraceptive, and hypericin isolated from Saint John’s wort (Hypericum perforatum) extract, is
used as an antidepressant [21].
OH
HO
H
C
3
CH
3
Gossypol Hypercin
Fig. 4.3: Gossypol and hypericin.
CH
O
OH
OH
3
H
C
3
H
O
OH
OH
C
CH
3
3
HO
HO
HO
O
HO
OH
O
CH
CH
3
OH
3
Another natural substance of oriental origin is artemisinin isolated from Artemisia
annua, a plant known and used in Chinese medicine, and whose structural complex-
ity has inspired new, useful drugs for the treatment of malaria. However, due its low
solubility and inadequate pharmacokinetic properties for therapeutic use, various
modified analogs have been synthesized, as shown in Fig. 4.4. SAR studies have
shown that the endoperoxide function in the natural compound is the pharmacophoric subunit. Through semi-synthesis, the active compounds β-artemether, arte-ether,
and sodium artesunate were obtained, and all without limitations in bioavailability
(Fig.4.4) [22].
58 Luciana Scotti*, Francisco J. B. Mendonça Júnior, Marcelo S. daSilva, Marcus T. Scotti
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CH
3
H
H3C
Fig. 4.4: Artemisinin derivatives.
O
O
H
H
O
O
C
3
β-Artemether R1 = CH
Arte-ether R1 = CH2CH
Sodium artesunate R1 = C(O)CH2CH2COONa
CH
3
O
R1
3
3
In silico methods or CADD (Computer-aided drug design studies) are increasingly
being used in both industry and in universities, they involve an understanding of the
molecular interactions from both qualitative and quantitative points of view. These
methods generate and manipulate three-dimensional (3D) molecular structures, calculate descriptors and the dependent molecular properties, model constructions,
and employ other tools that encompass computational drug research. Analysis of the
molecular structure of a given system allows relevant information to be extracted,
and to predict the potential of bioactive compounds [23].
Theoretical studies using in silico methods have aided in the process of drug
discovery. Technological advances in the areas of structural characterization, computational science, and molecular biology have contributed to faster planning of
new feasible molecules [24]. Chemoinformatic studies exist which show that a large
fraction of natural products are “drug-like” or at least, “lead-like” having structural
and physicochemical properties that render them as potential drugs or leads. Some
authors have even suggested a “natural product-likeness score” as a means to filter
large chemical databases and find new entities suitable for activity testing. The use of
natural products has been the subject of increasing interest in phytochemistry, biochemistry and other fields of research at the chemistry-biology-ecosystems interface.
4.3 Docking
Drug discovery is a lengthy and expensive process that can take up to 15years, and
cost upwards of billions of dollars. Most drug candidates fail in clinical trial. Of every
10,000 compounds tested, about one or two are marketed, the process wastes great
resources and effort. Traditionally, new drugs have been discovered through studies
of natural or synthetic compounds with biological activity. Today, theoretical methodologies have the advantages of both effectively reducing costs, and of speeding
up drug discovery; which results in earlier drug marketing. As examples of this, we
have: Captopril, from Bristol Myers-Squibb used for treatment of hypertension and
heart failure; Dorzolamide, an anti-glaucoma agent developed by Merck; Saquinavir, which is a protease inhibitor used for HIV therapy and produced by Hoffmann-
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