about targeted vs rational drug discovery

1. UNIT- 1
Biotechnology in Pharmaceutical sciences (BT- 510)
M.S. (Pharmaceutical Sciences)
NIPER- Guwahati
Biotechnology in pharmaceutical Sciences perspective

2. Traditional Drug Design
 Traditional drug discovery involves the origin of drug discovery
that evolved in natural sources and accidental events.
 It was not target based and not much systemized as today.
 Improved and advancements in pharmaceutical science and
technology has evolved to much more systemized modern drug
discovery.

3. Evolution in drug discovery
Era of Biologicals (vaccines and antibiotics)
Era of natural source based drug discovery
Era of semi synthetic drug discovery
Synthetic source based drug discovery
Genome based drug design and discovery + omics technology
Again focused on phytochemicals

4. Major events in traditional drug discovery
Progress in understanding the pathology of diseases was slow till mid 20th cent.
Anton van Leeuwenhoek identified bacteria by microscopy in 17th cent.
Louis Pasteur in 19th cent. Linked bacteria with diseases
Robert Koch identified microbial agents for TB, Cholera and typhoid in 19th cent.
1867- Joseph Lister- Germ theory of disease and advocated the use of soap containing phenol
1891- Pail Ehrlich- coined chemotherapy

5. Great periods of drug discovery

6. Methods for traditional drug design
1. Random screening
2. Trial Error method
3. Ethno-pharmacology approach
4. Serendipity method
5. Classical Pharmacology
6. Chemical structure based drug discovery (pharmaco-informatics)

7. 1. Random Screening & its contribution
A compound library is a collection of chemicals
that can be used for high-throughput screening and
other processes for drug/ industrial uses.
Recombinant technology and genomics enabled
target-based drug discovery, using methods
engineered with defined molecular targets

8. Ek compound ki screening hoti hai just to check its biological/ therapeutic action. Tow it is dedicated to only one
compound.

9. 2. Trial and error method

10. 3. Ethnopharmacology approach

11. Contribution of Ethno pharmacology

12. 4. Serendipity Method

13. Classical Pharmacology

14. Examples of FUNCTION based drug discovery

16. Chemical structure based drug discovery

17. Single compound synthesis
The traditional method of medicinal chemistry
involved the preparation, purification and
characterization of individual compounds.
Further in modern drug discovery it replaced by
combinatorial drug discovery

18. Rational Drug Design

19. Target Identification is the identification of a specific target with the generation of scientific
evidence that a manipulatable target is involved in some significant way in a disease process
A Valid Target is a target that when modulated pharmacologically, provides meaningful efficacy
and acceptable safety for specific human disease in long- term clinical usage.
Target Validation is the process of demonstrating in an experimental trial that engaging the target
provides statistically meaningful therapeutic benefit with acceptable safety for a given indication.
Target Qualification is preclinical or limited clinical studies prior to well- powered clinical trials,
that establish the scientific validity and safety of a drug target; it is part of the continuum of target
validation.
Target Identification and Validation: First step of rational
drug design

20. Next step: Lead optimization
Screening of molecules Hit identification SAR Lead identification
Lead optimization
Target validation
Hit identification is the first committed step for a successful drug
discovery project. In this process, the right small molecules, also called
hits, which binding to the target and modifying its function are identified.
Lead compounds are chemical compounds that show desired
biological or pharmacological activity and may initiate the
development of a new clinically relevant compound

21.  Lipinski's rule of five also known as the Pfizer's rule of five or simply the rule of
five (RO5) is a rule of thumb to determine if a chemical compound with a certain
pharmacological or biological activity has properties that would make it a likely
orally active drug in humans.
Lipinski's rule of five
 The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that
most orally administered drugs are relatively small and moderately lipophilic molecules.
 The rule describes molecular properties important for a drug's pharmacokinetics in the human
body, including their absorption, distribution, metabolism and excretion (ADME).
 However, the rule does not predict if a compound is pharmacologically active.

22. Lipinski's rule states that, in general, an orally active drug has no more than
one violation of the following criteria:
NMT 5 hydrogen bond donors (the total number of nitrogen–
hydrogen and oxygen–hydrogen bonds)
NMT 10 hydrogen bond acceptors (all nitrogen or oxygen atoms)
A molecular mass less than 500 daltons
An octanol-water partition coefficientlog P not greater than 5
Lipinski's rule of five

23. The rule is important to keep in mind during drug discovery a
pharmacologically active lead structure is optimized step-wise to
increase the activity and selectivity of the compound as well as to
ensure drug-like physicochemical properties are maintained as
described by Lipinski's rule.
Candidate drugs that conform to the RO5 tend to have lower
attrition rates during clinical trials and hence have an increased
chance of reaching the market.

24. Lead-like
During drug discovery, lipophilicity and molecular weight are often increased in order to improve
the affinity and selectivity of the drug candidate. Hence it is often difficult to maintain drug-
likeness (i.e., RO5 compliance) during hit and lead optimization.
Hence it has been proposed that members of screening libraries from which hits are discovered
should be biased toward lower molecular weight and lipophilicity so that medicinal chemists will
have an easier time in delivering optimized drug development candidates that are also drug-like
Hence the rule of five has been extended to the Rule of Three (RO3) for defining lead-like compounds.
A rule of three compliant compound is defined as one that has:
 octanol-water partition coefficient log P not greater than 3
 molecular mass less than 300 daltons
 not more than 3 hydrogen bond donors
 not more than 3 hydrogen bond acceptors
 not more than 3 rotatable bonds
Rule of Three (RO3)

25. Rational Drug design: Cimetidine
Starts with a validated biological target and ends up with a drug that optimally
interacts with the target and triggers the desired biological action.
Problem: Histamine triggers release of stomach acid
Solution: Need histamine antagonist to prevent stomach acid release by histamine
Validated target: Histamine

28. • 3D structure of biological target (receptor-based drug design)
• Structure(s) of known active small molecules (pharmacophore-
based drug design)
• Computer assisted drug design (CADD)
• Molecular graphics
• Pattern recognition
• Receptor fit
Rational Drug design: Approaches

29. 1. Receptor-based Drug design

30. 2. Pharmacophore-based Drug design

34. DRUG TARGET IDENTIFICATION OF
HEPATITIS B

39. • The virus attaches to membrane receptors
of host cell.
• cccDNA formation occurs.
• mRNA synthesis occurs and is transported
to cytoplasm.
• P-protein synthesis occurs and encapsulation
occurs.
Viral Replication Cycle

48. Stages of modern drug discovery

49. Drug Discovery and Development: All Four Stages
Source: www.nebiolab.com/drug-discovery-and-development-process/