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4.Selection of a Lead Molecule From Available Pool

The document outlines the process of selecting a lead molecule for drug development, starting with high-throughput screening (HTS) to identify potential candidates, followed by hit identification and optimization to enhance their properties. It emphasizes the importance of selectivity in drug targeting and discusses the role of medicinal chemistry techniques in optimizing lead candidates. Additionally, it highlights the significance of the Orphan Drug Act and the potential benefits of utilizing combinatorial chemistry and rational drug design in the development of new therapeutics.

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9 views32 pages

4.Selection of a Lead Molecule From Available Pool

The document outlines the process of selecting a lead molecule for drug development, starting with high-throughput screening (HTS) to identify potential candidates, followed by hit identification and optimization to enhance their properties. It emphasizes the importance of selectivity in drug targeting and discusses the role of medicinal chemistry techniques in optimizing lead candidates. Additionally, it highlights the significance of the Orphan Drug Act and the potential benefits of utilizing combinatorial chemistry and rational drug design in the development of new therapeutics.

Uploaded by

palwashasahar0
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Selection of a lead molecule

from available pool


Screening
• Screening is the initial step in the process of selecting a lead molecule.

• It involves the use of high-throughput screening (HTS) techniques to


identify molecules that have the potential to bind to the target protein.

• HTS involves testing a large number of compounds against the target


protein using various assays, such as biochemical, cellular, and functional
assays.

• The aim is to identify molecules that show high affinity and selectivity for
the target protein.
Hit Identification
• Once the screening is complete, the compounds that show promising
results are selected as hits.
• These hits are then subjected to further testing to determine their
potency, selectivity, and pharmacological properties. This process is
known as hit identification
Hit-to-Lead Optimization
• Hit-to-lead optimization is the process of selecting a hit molecule that
has the potential to become a lead molecule.

• This involves the use of medicinal chemistry techniques to modify the


hit molecule's chemical structure to improve its potency, selectivity,
and pharmacokinetic properties. The aim is to create a molecule that
has the potential to become a lead molecule.
Lead Optimization
• This involves the use of various medicinal chemistry techniques, such
as structure-activity relationship (SAR) studies, pharmacophore
modeling, and molecular docking. The aim is to create a molecule
that has the potential to become a drug candidate.

• Structure-activity relationship (SAR) is a fundamental concept in pharmaceutical sciences that explores the correlation between
the chemical structure of a compound and its biological activity. By systematically modifying the chemical structure of a compound
and assessing its activity, researchers can identify key structural features that influence its pharmacological effects. SAR studies
help in designing and optimizing drug candidates with improved potency, selectivity, and safety profiles, ultimately aiding in the
development of more effective medications.
• Pharmacophores are specific three-dimensional arrangements of atoms or functional groups within a molecule that are responsible for its biological activity by interacting with
complementary sites in a target biomolecule, such as a receptor or enzyme. These structural elements determine the molecule's pharmacological properties, including its affinity
and specificity for the target, as well as its mode of action. Pharmacophore mapping helps in drug design by identifying key features necessary for activity, guiding the
development of new compounds with optimized pharmacological profiles.
Steps need to be considered during
identification of a lead compound
1. Choosing the disease
Steps need to be considered during
identification of a lead compound
1. Choosing the disease
2. Choosing a drug target
Steps need to be considered during
identification of a lead compound
1. Choosing the disease
2. Choosing a drug target
3. Identifying a bioassay
Selectivity is Important!

• e.g. targeting a bacterial enzyme, which is not


present in mammals, or which has significant
structural differences from the corresponding
enzyme in mammals
Identifying a Drug Target (cont.)
• Example: In addition to their being able to inhibit the uptake of
noradrenaline, the older tricyclic antidepressants were observed to
“incidentally” inhibit serotonin uptake. Thus, it was decided to prepare
molecules which could specifically inhibit serotonin uptake. It wasn’t clear
that this would work, but it eventually resulted in the production of fluoxetine
(Prozac).

HO

N NH2
F3C
HN

CH3 O
N N
H
H3C
serotonin prozac

Imipramine
(a classical tricyclic antidepressant)
Steps need to be considered during
identification of a lead compound
1. Choosing the disease
2. Choosing a drug target
3. Identifying a bioassay
• It is necessary to have a quick assay for the desired
biological activity and to be able to separate the
bioactive compound from the other inactive
substances
• Lastly, a structural determination will need to be
made
Simultaneously, Chemistry is Improving!

• This is necessary, since,


ultimately, plants and natural
sources are not likely to provide
the cures to all diseases.
• In a process called “combinatorial
chemistry” large numbers of
compounds can be prepared at
one time.
• The efficiency of synthetic
chemical transformations is
improving.
• Synthesize analogs of the lead
• Identify Structure-Activity-Relationships (SAR’s)
• Synthesize analogs of the lead
• Identify Structure-Activity-Relationships (SAR’s)
• Patent the drug
• Continue to study drug metabolism
• Continue to test for toxicity
• Design a manufacturing process
• Carry out clinical trials
• Market the drug
The Orphan Drug Act

• The Orphan Drug Act of 1983 was passed to encourage


pharmaceutical companies to develop drugs to treat
diseases which affect fewer than 200,000 people in the
US
• Under this law, companies who develop such a drug
are entitled to market it without competition for seven
years.
• This is considered a significant benefit, since the
standards for patent protection are much more
stringent.
Finding the Lead (cont.)

Using Someone Else’s Lead


• Design structure which is similar to existing lead, but
different enough to avoid patent restrictions.
• Sometimes this can lead to dramatic improvements in
biological activity and pharmacokinetic profile. (e.g.
modern penicillins are much better drugs than original
discovery).
The mapping of the human genome
should help!
• In the past, many medicines (and lead compounds) were
isolated from plant sources.
• Since plants did not evolve with human beings in mind,
the fact that they posses chemicals which results in
effects on humans is incidental.
• Having the genetic code for the production of an
enzyme or a receptor may enable us to over-
express that protein and determine its structure and
biological function. If it is deemed important to the
disease process, inhibitors (of enzymes), or
antagonists or agonists of the receptors can be
prepared through a process called rational drug
design.
Problems can arise

• Example: The chosen target, may over time, lose its


sensitivity to the drug
• Example: The penicillin-binding-protein (PBP) known to
the the primary target of penicillin in the bacterial
species Staphylococcus aureus has evolved a mutant
form that no longer recognizes penicillin.

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