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1. DRUG
DISCOVERY
AND
DEVELOPMENT

2. The Success History of Natural Products in
Drug Discovery

3. HERBAL DRUGS FOR
ALZHEIMER'S DISEASE

5. The 2015 Nobel Prize in Physiology
or Medicine was awarded to
Professor Youyou Tu for her key
contributions to the discovery of
artemisinin.
 Tu Youyou turned to Chinese medical texts from the
Zhou, Qing, and Han Dynasties to find a traditional
cure for malaria, ultimately extracting a compound –
artemisinin – that has saved millions of lives. When she
isolated the ingredient she believed would work, she
volunteered to be the first human subject.

6. Do you know about drug development life cycle?
And, what is drug development process timeline?
For a new drug to get approved in the US, it takes ~12-15
years! That’s roughly 1/3rd of our entire professional
career. Next, how much investment do you think is
required for drug discovery design and development to
bring a new drug to market? A colossal sum of money,
~$1 billion, that’s equivalent to employing 665+
employees at the annual salary of $100k for 15 years.

7.  The complexity in drug development has
increased manifolds over the past 40 years,
requiring preclinical phase of drug
development, investigational new drug (IND)
application, and complete clinical testing
before marketing approval from the FDA.
 Generally, new drug applications (NDAs) or
biologics license applications (BLA)
are reviewed comprehensively before
approval, and then drug performance is
resubmitted to regulatory agencies for post-
marketing studies.
 The overarching goal is to bring more
efficient and safer treatments to the patients
as quickly as possible after a thorough
medical evaluation.

8.  Drug discovery research is how new medications are discovered. Historically, drug discovery, design, and development
mostly started with identifying active ingredients from traditional medicines or purely by chance. Later, classical
pharmacology was used to investigate chemical libraries including small molecules, natural products, or plant extracts,
and find those with therapeutic effects.

9. Target Identification And Validation
During the early stages of drug discovery
for a certain disease, the underlying
molecular mechanisms behind the disease are
studied. These studies include identifying
the cellular and genetic factors involved
in the disease, followed by the
identification of potential targets. In
order to ensure that the biological target
is involved in the disease, in
vitro (isolated cells) and in vivo (animal
models) tests are performed. This is also
known as the target validation stage.
Modern target validation often involves a
combination of in vitro, in vivo, and in
silico (performed with a computer)
studies. The results of the target
validation stage can assist in lead
compound identification.

10. Lead compounds are chemical compounds that
show desired biological or pharmacological
activity and may initiate the development of a
new clinically relevant compound. Lead
compounds are typically used as starting points
in drug design to give new drug entities. Drug
design strategies can be used to improve the
compound’s pharmacodynamic and
pharmacokinetic properties.
Possible sources of lead compounds and novel
drugs include:
1.Natural products
2.Chemical libraries
3.Computational medicinal chemistry
What are Lead Compounds ?

12. Epipedobates tricolor
Bothrops jararaca

14. Precision microplate pipetting

16. Lead Optimization
In the lead optimization (LO) process, the lead compounds
discovered are synthesized and modified to improve potency
and reduce side effects. Lead optimization conducts
experimental testing using animal efficacy models and ADMET
tools, designing the drug candidate.
The drug discovery process gets narrowed
when one lead compound is found for a
drug candidate, and the process of drug
development starts

18. Formulation Optimization & Improving Bioavailability
Formulation optimization is ongoing throughout pre-clinical and clinical stages. It ensures drugs are delivered to the
proper place at the right time and in the right concentration. Optimization may include overcoming solubility

25. Drug Design — A Special Case Study
On Malaria

26. Malaria
Malaria is an infectious disease known since ancient times. The name comes
from the words ‘mala aria‘ meaning ‘bad air’. Malaria was associated with regions
that are badly drained, swamps, and marshes. The disease is caused by a
protozoal parasite (genus plasmodium), which is carried by female mosquitos
(genus Anopheles). Species of genus plasmodium associated with malaria
include vivax, malariae, falciparum, and ovale. Plasmodium falciparum poses the greatest
danger to humans and it is known to affect up to 65% of an infected person’s
erythrocytes. Transmission between infected mosquitos and humans occur through

27. Controlling & Treating Malaria
Natural compounds from the bark of the cinchona tree,
most notably quinine was observed to exhibit
antimalarial activity. Until the development of
synthetic derivatives (ie. 4-aminoquinoline
antimalarials), quinine continued to be the first
choice to treat malaria in the West. However, quinine
is associated with side effects such as diarrhea. 4-
aminoquinoline antimalarials such as amodiaquine and

28. Antimalarial Drug Discovery: From Quinine to the Dream
of Eradication
During the Vietnam War 1962–1975, there
were 24,606 cases of malaria, an estimated
391,965 sick-days because of malaria, and 46
deaths due to malaria. With the worldwide
resurgence of malaria, the spread of drug-
resistant strains of Plasmodium falciparum, the
emergence of chloroquine-resistant Plasmodium
falciparum
Malaria felled more combatants during the
war than bullets. The disease reduced the
combat strength of some units by half. Over
40,000 cases of Malaria were reported in US
Army troops alone between 1965
Men Against Mosquitoes: Malaria in War | Defense Media

29. The herb, Artemisia annua has been used by Chinese herbalists for over two millennia.
It was not until after the 1970s when the active principle was identified by Chinese
scientists and was called qinghaosu (artemisinin). Clinical studies performed on
members of the Chinese army that are affected by malaria delivered excellent results.
The experiments demonstrated that qinghaosu had excellent therapeutic efficiency.
Most notably, chloroquine-resistant plasmodium falciparum were affected by the
active compound of A. annua

30. The researchers who discovered qinghaosu not only had problems with production and formulation. They were
also restricted from disseminating their findings to the rest of the world. External access to the purified drug was
generally restricted by the Chinese government at the time. Organisations with resources to study A. annua such
as the World Health Organisation (WHO) were denied access to the herb and the drug. The results of the studies
were eventually published on the Chinese Medical Journal where the information became more accessible to
those outside China (Chinese Medical Journal, 1979, 92 (12), pp 811-816).
Bottleneck

31. Many scientists were initially skeptical of artemisinin’s usefulness as
a drug because of the compound’s unstable appearance. The
trioxane ring which contained an endoperoxide bridge was cited to
be an unstable feature. It is now generally believed that the
trioxane ring is central to the compound’s activity.
Drug Design

32. Artemisinin serves as a lead compound for the development of
new antimalarials with improved properties. The therapeutic
utility of the lead itself is limited by poor physicochemical
properties such as water solubility. The lactone group can be
reduced using reducing agents such as sodium borohydride
(NaBH4 ). The reduced form, dihydroartemisinin is used to
prepare semisynthetic prodrug derivatives that are more
water-soluble.
The hydroxyl group can be alkylated to give oilsoluble ether
derivatives such as artemether and arteether. Esterification of
the hydroxyl with succinic acid gives the water-soluble
derivative, artesunate.
Artemether is generally given to patients through
intramuscular injections. Artesunate can be administered
intravenously and orally. Artemisinin semisynthetic derivatives
are often administered alongside other antimalarials to
decrease the likelihood of the development of resistance.

33. The synthesis of analogues, as well as the study of metabolites allowed researchers to investigate
structure-activity relationships. Studies of artemisinin analogues such as deoxyartemisinin which do not
contain the endoperoxide bridge, showed vastly reduced biological activity. In essence, structure-activity
relationships studies of analogues led to the conclusion that the trioxane ring containing the
endoperoxide bridge is part of the pharmacophore and is crucial to antiplasmodial activity

34. Moreover, derivatization at the carbonyl lactone demonstrated that it is a possible region of modification that can be
manipulated in order to improve pharmacokinetic properties. This was demonstrated by the semisynthetic prodrugs.
Compared to artemisinin itself, artemether, artesunate and dihydroartemisinin are more active.

35. Arteflene, which is based on another endoperoxide-containing compound known as
yingzhaosu, exhibited antimalarial activity about half of artemisinin. Arterolane, a
synthetic trioxolane with better pharmacokinetic properties than semisynthetic
artemisinins, is currently in clinical trials.
Artabotrys hexapetalus