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CHAPTER 13
Ayurvedic Knowledge Inspired
Approach to Modern Drug
Discovery
y
PREMALATHA BALACHANDRAN
National Center for Natural Products Research, Research Institute of
Pharmaceutical Sciences, School of Pharmacy, University of Mississippi,
MS 38677, USA
Email: prembala@olemiss.edu
13.1 Introduction
Since the beginning of humanity, our goal has been to alleviate diseases or
their symptoms and we have focused our attention on nature to discover
medicines for these diseases. From a manufacturing point of view, for a drug
to be successful it should be stable, less complicated, easily producible in
large quantities, and deliverable at affordable costs. From efficacy’s stand-
point, a drug should exhibit good ADMET characteristics like absorption,
distribution, metabolism, excretion, and toxicity, and should be able treat
the targeted disease with specific efficacy.
1
In the pharmaceutical field, drug discovery (DD) is an innovative multi-
disciplinary process of finding new medications for any disease or health
y
Disclaimer: Opinions, views, and recommendations expressed in this chapter are solely those of
the author and do not express the views or opinions of the National Center for Natural Products
Research, the School of Pharmacy, or the University of Mississippi.
Chemistry, Biological Activities and Therapeutic Applications of Medicinal Plants in Ayurveda
Edited by Augustine Amalraj, Sasikumar Kuttappan and Karthik Varma A. C.
r The Royal Society of Chemistry 2023
Published by the Royal Society of Chemistry, www.rsc.org
325
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problems. Historically, this DD process was s tarted from the active in-
gredients of traditionally-used medicines or through accidental surprise
discoveries.
2
But in recent days, it is done through a well-planned process
involving bioactivity guided fractionation and isolation of thousands of pure
compounds. These compound libraries are screened through high
throughput methods against several molecular targets, and interesting leads
from this initial screening process are subjected to pre-clinical trials in
animals for efficacy. The modern drug discovery process involves the opti-
mization/refinement of those lead compounds to augment their binding
affinity, specificity, efficacy, stability, and favorable bioavailability. Potential
compounds that pass through this rigorous process enter the drug devel-
opment stage and further proceed in clinical trials; the average development
time is about 12 years.
3
Ayurveda, a traditional Indian system of medicine not only includes
medical practices and beliefs related to the prevention and the treatment of
diseases but also overall holistic health, well-being, and spiritual healing.
Ayurveda dates to 3000 BC and its classic texts Atharvaveda, Charak Samhita,
and Sushrut Samhita describe more than 700 medicinal plants. In India,
more than 3000 plants possess established medicinal values. Additionally,
over 6000 plants are used as traditional and folk medicines.
4
Ayurvedic drugs
have been time tested over centuries and developed based on extensive
knowledge on pharmacognosy, medicinal chemistry, pharmacology, and
clinical case studies that are continuing to be proven useful for modern drug
discovery. Ayurvedic medicines are composed of a unique combination of
natural products (herbs, minerals, metals in oxidized non-toxic forms, and
rarely animal products) and these components provide a strong basis for the
discovery of novel modern drugs which could either be a single molecule
drug or a combo medicine.
Millions of people in developed countries use some form or other al-
terative medicines for t herapeutic, food-additive, and cosmetic benefits.
This has led to a new revolution in the dr ug industry and leading
pharmaceutical companies are moving their attention to natural products-
based drug discovery. New strategies with advanced biological ap plications
are being established to facilitate the process.
5
Currently, modern medicine
uses natural products in scient ific ways and these products have contrib-
uted to a fair share of approved drugs in the 21st century and the approach
is also shifting towar ds combi ning ex isting agents b ased on traditional
knowledge.
6
13.2 Overview of the Modern Drug Development
Process
Jean et al.
2
described this process in three major steps viz., target identifi-
cation, i.e., identifying the direct molecular target and its validation,
screening for desired lead compounds, and their optim ization.
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13.2.1 Target Identification
Initial stages of drug discovery start from this step and various sectors such
as academic researchers, scientists, physicians, and commercial pharma-
ceutical companies, all play a significant role in the identification of these
disease targets. For a drug to be considered safe enough, it should fulfill
both clinical and commercial requirements, in other words, ‘‘druggable’’.
The first step in this drug discovery process begins with the identification of
possible therapeutic targets (a gene or protein), not only with a unique role
in the disease but is also safe and effective. This is followed by the charac-
terization of their mechanism of action and ability to attack or modify the
target gene, responsible for the disease. The ideas for drug targets are gen-
erated from basic science research, literature searches, function al screening,
pathway and phenotypic analysis, or data mining using bioinformatics.
Among these techniques, bioinformatics data mining has an advantage as it
can identify, select, and prioritize potential disease targets and this techni-
que could advance with the development of artificial intelligence methods.
After this critical step, the identified targets are tested for their ability to
demonstrate their therapeutic effect on the disease onset or its progression.
Functional analysis or validation processes are performed through the an-
alysis of signaling pathways, cell-based in vitro assays, protein interactions,
and genetic approaches to evaluate the relationship between the pharma-
cology and the phenotype of interest, and would determine the safety profile
of the target.
2,7,8
13.2.2 Lead Compound Screening
This stage could be performed via two different methods of screening. For
knowledge-based screening, large libraries of test compounds, selected
based on prior knowledge like literature evidence, traditional use, patent
precedents, etc. are screened using automated robots through high
throughput screening (HTS). As HTS is time and cost efficient, millions of
assays could be performed with great accuracy in a short period of time. HTS
coupled with molecular biology tools are widely adopted to identify hit/lead
compound(s) with a desired biological or pharmacological activity, and the
compounds emerging from these screening processes exhibit high potential
to be developed as a drug. Another method called ‘‘focused screening’’ in-
volves screening of a smaller pool of compounds narrowed on the basis of an
existing proven activity with the drug target.
2,7,8
13.2.3 Lead Compound Optimization
Once identified, these lead compounds are optimized for potency, select-
ivity, toxicity, safety, mechanism of action, and biodistribution. At this stage,
the compounds which have strong toxicity, low bioavailability, and improper
pharmacokinetics are modified with desired characteristics before moving
Ayurvedic Knowledge Inspired Approach to Modern Drug Discovery 327
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on to the developmental stage which includes pre-clinical studies in animals
and several phases of clinical trials. The drugs that have emerged success-
fully after phase 3 clinical trials can be filed for NDA (New Drug Application)
with the FDA for review and approval. NDA approval opens the door for
commercial production and marketing and the drug eventually becomes
available for use. The FDA would still continue to monitor drug safety and
other issues even after the drug has been on the market for several years.
2
13.3 Challenges in the Modern Drug Discovery
Approach
According to a 2016 study by the Tufts center for the study of Drug Devel-
opment, the approximate cost for pharmaceutical companies to develop a
new drug (from screening to US FDA approval) is estimated to be around
$1.395 billion US dollars just for out-of-pocket costs. It costs $2.558 billion
US dollars when we calculate complete capitalization costs.
9
Based on the
availability of resources and methodological differences this cost could be
different. Another study shows the median cost of developing a cancer drug
is $648 million in out-of-pocket costs and $757 million in capitalized costs.
10
Furthermore, data shows that developing non-orphan drugs is expensive
compared with orphan (rare disease) drugs.
11
These costs are largely due to
the various phases of clinical trials required to generate a safety profile for
the drugs.
13.4 Ayurvedic Drug Discovery
13.4.1 Basic Principles of Ayurveda
Ayurveda means ‘‘the science of life’’ and it is known as the ‘‘mother of all
healing’’. It promotes health maintenance by paying close attention to the
balance in one’s life, right thinking, healthy die t, lifestyle, and the use of
medicinal herbs at the appropriate time and quantity. All human beings are
unique in their own fingerprint or constitution, which is a particular form of
energy – a combination of ph ysical, mental and emotional characteristics,
and behavior. This constitution is determined at the time of birth by several
factors, including external and internal. These factors influence balanced
health and any disturbance to this balanced state is reflected as a change in
one’s constitution leading to a diseased condition. Ayurvedic physicians
have the expertise to understand these factors and take appropriate action to
nullify or minimize the effects or eliminate the causes of imbalance and re-
establish one’s original constitution. According to Ayurveda, ‘‘balance is the
natural order while imbalance is disorder’’; ‘‘health is order while disease is
disorder’’, and there is a constant oscillation between order and disorder.
12
Ayurveda identifies 3 basic functional principles Vata , the subtle energy
associated with movement, Pitta, the energy of digestion based on the body’s
metabolism, and Kapha, the energy that forms the body’s structure
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(Tridoshas). According to Ayurvedic philosophy, the entire cosmos is an
interaction of the energies of the five great elements – space, air, fire, water,
and earth. Vata, pitta, and kapha are combinations and variations of these
elements that demonstrate as patterns present in all human beings.
12
‘‘Panchakarma therapy’’ in Ayurveda focuses on body rejuvenation, and
cleansing leading to longevity of life. As the name implies, the Pancha karma
is composed of five karmas (actions) that are used for the removal of toxic
substances from our body tissues and fluids. They are the Virechan (pur-
gation using powders, pastes, or decoction), Vaman (forced therapeutic
emesis using medicines), Basti (use of enemas prepared from medicated
oils), Rakta moksha (detoxification of blood and body fluids), and Nasya
(nasal administration of medicines like decoctions, oils, and fumes).
13
It is always surprising to realize the wealth of knowledge possessed by our
ancestors. This oldest system of medicine was subdivided into eight dis-
ciplines and they are called ‘‘A
¨
shtanga Ayurveda’’. They are Kayachikitsa
(internal medicine treatment), Bhootavidya (treatment of psychological dis-
orders), Kaumar Bhritya (pediatric treatment), Rasayana (study of geriatrics),
Vajikarana (treatment through aphrodisiacs and eugenics), Shalya (surgical
treatment), Shalakya (otorhinolaryngological and ophthalmological treat-
ment), and Agada Tantra (toxicological studies).
13
This subdivision enables
Ayurvedic physicians to earn expertise in a particular field and focus and
adopt various treatment modalities. Also, this classification helps modern
scientists to narrow the target screening process purely based on this
knowledge.
13.4.2 Integrating Ayurvedic Principles into Modern Drug
Discovery
Although use of natural products for health improvement or for the treat-
ment of diseases, has been described throughout history in the form of
traditional medicines and various remedies, their bioactive natural in-
gredients (active constituents) are largely unidentified.
14
The ultimate goal
of any drug discovery is to achieve safe, effective, personalized medicine and
the depth of ayurvedic knowledge offers immense solutions for many dis-
eases and remains an appropriate approach, but unfortunately this ancient
wisdom and depth of knowledge are still not extensively explored through
modern scientific methodologies. The medicinal plants that have been used
in Ayurveda for centuries could provide a platform for modern drugs and
advanced technologies could be developed from ayurvedic principles.
Pharma companies from various countries are pivoting their strategies,
paving a way for new herbal-based therapeutic channels from what has long
been known as traditional remedies.
15
As the safety profile of these medi-
cines is well established, this approach has added the benefit of bringing
patients closer to nature while cutting down the cost and time of drug
development.
Ayurvedic Knowledge Inspired Approach to Modern Drug Discovery 329
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Current trends in the drug discovery process, although being revolution-
ized by the developments of advanced technologies, have their roots in
natural resources (plant- or mineral-based). Numerous examples are avail-
able among modern drugs that were developed from herbal-based resources.
One such classic example is opium-based morphine, which was produced
from the latex of the poppy plant, Papaver somniferum, 200 years ago. In
these footsteps, several drugs developed from natural/plant sources have
certainly revolutionized the entire world. These drugs, such as antibiotics
(e.g., erythromycin, penicillin, tetracycline), antiparasitics (e.g., avermectin),
antimalarials (e.g., quinine, artemisinin), hypolipidemic (e.g., lovastatin and
analogs), immunosuppressants for organ transplants (e.g., rapamycin, cy-
closporine), anticancer drugs (e.g., irinotecan, paclitaxel), and antidiabetic
drugs (e.g., metformin)
16
have saved millions of lives.
High throughput screening methods, molecular docking in silico methods,
understanding of signal transduction pathways and their interconnection
with various disorders, and advanced tools in molecular biological techni-
ques have paved a new way in drug discovery methodologies.
Despite the availability of these, only 410 drugs were approved by the US
FDA over the past de cade. Although an average of 40 drugs per year, the
highest number of novel drugs approved any given year was 59 (in 2018).
17
These low numbers are largely due to the strict regulatory processes, espe-
cially towards the safety profile aspect of new drugs as it cannot be evaluated
with certainty for several years after its market launch.
18
Due to these
challenges in modern drug discovery, Ayurveda’s basic principles,
experiential wisdom, holistic appr oach and systemic database could offer
efficient drugs
19
and there has been a massive reemergence of interest in the
Ayurvedic system of medicine.
20
The therapeutic principles of Ayurveda
focus on Prakriti and tridoshas. Prakriti or body constitution determines how
an individual could respond or react to medications, environmental con-
ditions, and dietary factors. ‘Ayurgenomics’, recent research in exploration,
bridges this gap between genomics and Ayurveda and ser ves as a new tool to
understand the differences between individuals in responses to therapies in
various diseases.
21
As it could evaluate inter-individual genetic variances in
patients from identical ethnic backgrounds,
13
it offers the basis for gene
targeted therapy and facilitates the development of customized therapeutic
approaches.
22,23
Ayusoft, a database developed for various Ayurvedic drugs,
includes the network of diet patterns , lifestyles, diseases, and treatment
principles.
24
This advanced, handy software is very helpful as a quick index
tool for practitioners to refer to and access information for their diagnosis
and treatme nt. Herboprint uses three-dimensional High-Performance
Liquid Chromatography (HPLC) and it is in the process of developing
techniques for bioactivity-based botanical standardization.
25
Rotti et al.,
26
have done extensive research on finding a correlation be-
tween the concept of prakriti in Ayurveda and modern-day science. One of
the repo rts indicate the correlation of prakriti with the Body Mass Index
(BMI) and birthplace of individuals. In another study, the individuals with
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various prakriti types, viz. vata, pitta, and kapha constitutions were evaluated
and compared based on their molecular differences, as these mechanisms
play a significant role in the response to the treatment of every individual. In
addition, these authors have also classified human population with respect
to their DNA methylation signatures, and compared them with the tradi-
tional Ayurveda concept of prakriti.
27
In a study involving a genome-wide
SNP (single nucleotide polymorphism) consisting of 262 male volunteers,
belonging to three different prakritis, they found a classical association
between the PGM1 gene and energy production and this gene is more
homogeneous in the pitta prakriti, than the kapha or vata prakriti.
28
These
scientific approaches to ayurvedic concepts serve as a catalyst and motivate
modern scientists to furthe r explore the scientific basis of ayurveda.
13.4.3 Suggested Sequential Steps in Ayurvedic Drug
Discovery
Although traditional medicine like Ayurveda serves as a rich source of
therapeutic leads and provides fertile ground for modern drug develop-
ment,
1
not all the potential lead molecules from plant sources can enter the
drug development process. Success in identifying a new biologically active
plant-based natural product can be influenced by several factors, including
random or non-random plant selection, virtual screening through compu-
tational methods, in vitro screening through biological methods (high
throughput screening), screening from ethnomedical knowledge and use of
other approaches like ecological approaches, in vivo toxicity, bioavailability,
and SAR relationships. A review of natural products estimates the presence
of about 300 000 to 500 000 species of plants, but less than 10% of these
plants have been studied for 1 or more bioactivities.
14
Using traditional
Ayurvedic knowledge to explore these medicinal plants offers a new in-
novative strategy in the drug discovery process and facilitates not only the
development of new single drug candidates but also synergistic botanical
formulations as well.
5
The flow chart depicted in Figure 13.1. proposes a
graphical summary of the sequential steps for the drug discovery from the
plants used in Ayurveda. This concept was partially adapted from Farns-
worth et al. on the study of plants from traditional medicine.
29
The problems
and possible solutions in this process are provided in Table 13.1.
30
13.4.4 Reverse Pharmacology: Promising Road to Ayurvedic
Drug Discovery
Reverse pharmacology is an accomplished scientific approach to develop
new drugs utilizing available knowledge, wisdom, and guidance from tra-
ditional medicines through sound clinical and pre-clinical research studies.
As the name implies, it is a reverse process to modern drug discovery. As we
have seen earlier in this chapter, wh ile modern drug discovery begins with
Ayurvedic Knowledge Inspired Approach to Modern Drug Discovery 331
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