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since some clinical trials have been carried out within these study areas (Graefe et al., 2001;
Vareed et al., 2008; Yamaga et al., 2021).
7.6 CONCLUSIONS
Viruses are infectious agents that can cause pandemics causing thousands and even millions
of deaths; there are few viral diseases for which there is a specific antiviral treatment. In
most cases, the treatment is only symptomatic. On the other hand, most viruses change
continuously due to mutations in their genome, a phenomenon that can lead to the generation of resistance to the few currently existing antivirals. This is where the importance lies
that various types of products of natural origin have inhibitory properties against different
types of viruses, generating an encouraging outlook for the future formulation of specific
antiviral treatments. Some of these compounds have other properties that further increase
their therapeutic potential in diseases of viral origin; one of these properties is the antiinflammatory capacity that they possess, decreasing, for example, the secretion of proinflammatory cytokines that have been related to the development of hypovolemic shock.
Many aspects of the antiviral and anti-inammatory action mechanisms of many of
the compounds with therapeutic potential for viral diseases are still unknown; however,
little by little the pieces of the puzzle have been coming together, which will allow soon to
design specic treatments that help prevent the development of severe forms of some viral
diseases.
KEYWORDS
• natural products
• polyphenols
• polysaccharides
• viral infections
• viral diseases
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CHAPTER 8
Approaches to Develop Drugs from Natural Products
HIMANI SHARMA
1
1,*
, SHIVANI CHAUHAN2, KAVITA RANA3, and PREETI SHARMA
4
2
3
4
*Corresponding author
ABSTRACT
In the past, natural products (NPs) played a significant role in the development of pharmaceuticals, not only for the treatment of infectious and cancerous diseases but also for other
therapeutic conditions such as multiple sclerosis and cardiovascular diseases. The discovery
of new drugs is also hampered by factors such as profit and loss, partnerships, averages,
and NPs. These factors include technical challenges in isolation, characterization, and
optimization, which led to a decline in the pharmaceutical industry’s search for novel drugs
beginning in the 1990s. The use of molecular biological methods has recently expanded the
accessibility of new substances that are easily synthesized from sources such as bacteria,
yeast, or plants. In addition, NP scaffolds are being used in combinational chemistry procedures to build screening libraries that closely resemble drugs. We can conduct research in
the screening of novel compounds using software and databases to find NPs as a substantial
source for medication development by utilizing these technologies. Finally, it discusses
the creation of pharmaceuticals from plant-based NPs and the importance of innovative
technologies in next-generation drug discovery, pointing to the discovery of lead structures
as sources of anti-inflammatory chemicals.
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8.1 INTRODUCTION
The use of plant-based remedies to heal human illnesses has been reported for very long
ago. Most of the active components included in these medicines come from natural sources.
Prior to the advent of high-throughput screening (HTS) and the postgenomic era, it was
generally accepted that more than 80% of pharmacological substances were either natural
products (NPs) or directly derived from a natural chemical. Mesopotamian clay tablets
dated 2600 BC mention a number of plant species including licorice (Glycyrrhiza glabra)
opium (Papaver somniferum) and myrrh (Commiphora species). Nowadays, these plants
are still utilized either alone or in combination with other herbal treatments, to cure a
wide range of illnesses. Furthermore, a range of disorder have been and still are treated
with organic material sourced from natural sources. Both in their natural condition (as
pure pharmaceuticals or phytomedicine) and as building blocks for the development of
synthetic and semisynthetic counterparts with improved drug ability, these compounds are
used (Newman et al., 2000; Newman et al., 2003; Koehn and Carter, 2005). In past studies,
these recently authorized NP-based medications were fully discussed (Butler, 2008). For
example, elliptinium, galantamine, and huperzine are obtained from plants, microbes, and
animals. Other examples include artificial or semiartificial chemicals based on NPs such
as tigecycline, everolimus, telithromycin, micafungin, and caspofungin. They have a broad
range of chemical structures and have a number of medicinal uses, including anticancer,
anti-infective, and antidiabetic. Recently, natural small-molecule compounds have been
transformed into medicines, and their chemical properties have been studied (Figure 8.1).
FIGURE 8.1 Processes involved in the development of drugs from NPs.
⏎
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India has a reputation for having one of the largest reserves of medicinal plants among
extremely old civilizations. Over 8000 herbal remedies have been standardized by A yurveda.
The Charaka Samhita (700 BC) and the Sushruta Samhita (200 BC) specied attributes
and employed 1100 and 1270 species, respectively, to blend the remedies and usage. The
Atharvaveda (4500–2500 BC) listed 290 species. There were 67 therapeutic plants listed
in the Rigveda (5000 BC). These are still utilized in the Ayurveda medical systems for
traditional drug preparation (Joy et al., 2001). One plant known from Ayurveda is snakeroot, also known as Rauwola serpentina, which has been used for its calming properties
for ages. Currently, snakeroot’s active ingredients are frequently employed in Western
medicine to successfully treat high blood pressure (Kong et al., 2003). On this planet, there
are believed to be 250,000 higher plant species (angiosperms and gymnosperms). Only
6% of them apparently had biological activity screening done, while 15% reportedly had
a phytochemical analysis done (Verpoorte, 2000). Since 1994, it has been established that
around half of all new medications have been derived from natural resources, according
to an investigation of the origin of these drugs from 1981 to 2007. Small molecules are
naturally produced by plants, microbes, and animals. These molecules have been crucial
in the discovery of new drugs. Thirteen of the 69 novel small-molecule medications
that were acclaimed from 2005 to 2007 globally were either NPs or derived from them,
demonstrating the importance of such compounds for drug development and research (Ngo
et al., 2013). There are several instances of the development of novel medications from
plant sources. The presence of morphine in opium derived from ground-up poppy plant
(Papaver somniferum) seed pods dates back more than 200 years. After World War II,
pharmaceutical research expanded to include the screening of microorganisms for new
antibiotics as a result of the important discovery of penicillin in that era. Erythromycin,
antimalarials (e.g., quinine, artemisinin), tetracycline penicillin, lipid-regulating drugs
(e.g., lovastatin and its analogues), antiparasitics (e.g., avermectin), anticancer drugs (e.g.,
paclitaxel, irinotecan), and immunosuppressants for organ transplants (e.g., cyclosporine,
rapamycins) are just a few examples (Harvey, 2008).
Natural substances derived from botanical sources can fall into various categories,
such as biologically active substances used as direct therapeutic agents, lead substances
(with specic biological activity) for the development of more potent analogs, materials
whose structures could yield novel pharmacophore that could be made into medicine,
or chemical entities used as a marker for the standardization of crude plant extracts;
furthermore, herbal formulations can be created using herbal components such as plant
extracts. Compounds that have been separated from natural sources are characterized by
a lower ratio of aromatic ring atoms to total heavy atoms, more oxygen atoms, more
chiral centers, higher steric complexity and molecular rigidity, and more hydrogen bond
acceptors and donors. A wider variety of molecular characteristics are also present such as
partition coefcient, molecular mass, and various ring systems. Because of these unique
qualities of the molecules derived from natural sources, medicinal chemists never have
an easy time synthesizing analogs to increase potency and pharmacokinetic attributes and
decrease toxicity.
Following the proper procedure for biological screening and selection, extraction and
fractionation of active compounds, and phytochemical characterization to identify main
152
components for specic biological activity and nally development of various analogues
of the identied lead components through in silico and virtual screening techniques.
The current paradigm for drug discovery in big pharmaceutical businesses and technical
constraints in identifying a limited number of molecules with exceptional activity are the
two main causes of dispute in the development of innovative medications. The following
distinguishing characteristics of the chemicals that have been isolated from NPs are listed
by Koehn and Carter (2005):
• An increase in the number of chiral centers
• Large number of oxygen atoms
• Complexity of steric compounds
• Solvated the number of acceptors and donors of hydrogen bond
• Higher ratio of whole heavy atoms to aromatic rings
• A wide range of molecular characteristics, the octanol–water partition coefficient
including molecular mass, and the ring structure diversity
• Molecular masse’s rigidity
These distinctive properties of chemical entities of natural origin presented a number
of challenges when medicinal chemists began working on expanding analogues, whether
to improve absorption or to reduce toxicity and recover upon efcacy, which is frequently
done by the functional group, either addition or deletion of chosen functional groups.
According to a review by Ehrman
et al. (2007), a variety of bioactive plant compounds,
including alkaloids, limonoid, steroids, diterpenes, triterpenes, sesquiterpenes, monoter-
penes, isoavonoids, tannins, avonoids, lignans, polycyclic aromatics, aliphatic, coumarins, and simple phenolics, were isolated in China between 1911 and 2000. With avonoids
at 15%, triterpenes at 10%, and enduring others lower than that, and with the least potency
of limonoid, alkaloids can range from 20% to 15%.
A cautious hypothesis is that a sizable portion of naturally occurring chemicals
does not meet the “ drug similarity” requirement despite being physiologically active
and having an excellent absorption, distribution, metabolism, and excretion prole. To
help natural goods reach their full potential, the task is to establish a physiochemically
optimized NP library in accordance with direct generation. Lipinski et al. (2001) published
a straightforward list of estimated properties known as the “ rule of ve” for the treatment
candidates advancing to phase II clinical trials. The name of the rule comes from the fact
that it is one of four rules in an algorithm, several of which have cutoff values of ve
or multiples of ve. A candidate must have a molecular weight of under 500 Da, fewer
than ve hydrogen bond donors, fewer than ten hydrogen bond acceptors, and a partition
coefcient log p of under ve in order to qualify as a drug-like compound. The “ role
of ve” is designed to draw attention to potential bioavailability issues if two or more
qualities are broken. Paclitaxel would not have been a medicine in any way if Lipinski’s
criteria had been implemented. Since the “ rule of ve” is not applicable to chemicals
derived from natural sources, determining alternative druggability standards is extremely
challenging. Finding new druggability standards for natural chemical sources is the key
challenge (Table 8.1).