5. Docking as a target
identification tool
Docking: Computational search for energetically
favorable binding poses of a ligand with a receptor.
Find origins of ligand binding which drive
molecular recognition.
• Finding the correct pose, given a ligand and a
receptor.
• Finding the best ligand, given a database and a
receptor.
9. 1. Transgenic Animals
Transgenic animals are created by deliberately inserting a gene
into the genome of an animal. Recombinant DNA methodology
is used to construct the gene that is intended to express
desirable qualities during the growth and development of the
recipient animal.
Transgenic animal models allow unprecedented control over
manipulation and visualization of genes and gene products.
Transgenic rats as model are used for:
• Hypertension
• Atherosclerosis
• Alzheimer’s disease
10. 2. Antisense technology
In Antisense technology, synthetically produced complementary
molecules seek out and bind to messenger RNA (mRNA),
blocking the final step of protein production.
mRNA is the nucleic acid molecule that carries genetic
information from the DNA to the other cellular machinery
involved in the protein production.
By binding to mRNA, the antisense drugs interrupt and inhibit
the production of specific disease-related proteins.
11. 3. Chemical Genomics
Chemical genomics or chemogenomics, is the systematic
screening of targeted chemical libraries of small molecules
against individual drug target families with the ultimate goal of
identification of novel drugs and drug targets.
Typically, some members of a target library have been well
characterized where both the function has been determined
and compounds that modulate the function of those targets
have been identified.
14. 1. Physiological
Screening
A tissue-based approach and looks for a response
more aligned with the final desired in vivo effect as
opposed to targeting one specific molecular
component.
15. 2. High
Throughput
screening
Standard method for
drug discovery
1000’s of compounds
possess potential of
emerging as a new drug
are tested using
automated machines
Tested for their ability
to modify the
properties of a selected
biological target
Remove inactive
compounds at initial
stage and accumulate
active compounds.
The main goal is to
accelerate drug
discovery process by
screening large libraries
18. 1. Absorption
Strategies
• Animal studies (rat) – Very low throughput
• In situ intestinal models – Very low throughput,
expensive
• Intestinal epithelial barrier models
a) MDCK cell line
b) HT29 cell line
c) Caco-2 cell line
23. 4. Excretion
Strategies
In vivo excretion studies are not
usually performed in lead
optimization
In vitro models to investigate
renal excretion are very limited.
The primary in vitro renal
excretion model is the isolated
perfused rat kidney
24. 5. Insilico ADME
Strategies
Availability of massive ADME and PCK data in the
literature and within the pharmaceutical company
databases has led to the initiation of datamining
efforts in order to understand the SAR for ADME
properties.
a) Molecular Based Modeling
b) Data Based Modeling
26. Prediction of Drug Safety
1. In vitro methods
2. In vivo methods
3. Ex vivo methods
27. 1. In vitro methods
In vitro methods are complicated due to
• Difficulties of maintaining cells in culture
• Lack of understanding of the humoral and matrix
requirements
28. 2. In vivo methods
In vivo methods are focused on determining safe
doses for PCK (phase I) studies by measuring
tolerable and toxic doses
29. 3. Ex vivo methods
Ex vivo methods analyze tissues, tissue extracts, or
fluids from animals previously exposed to lead
candidates and the comparison of these results to
those derived from untreated animals.
31. Estimation of Starting
Dose for Phase I
Determine NOAEL (mg/kg) in toxicity
studies
Convert each animal NOAEL to HED
(based on body surface area)
Select HED from most appropriate
species
Choose safety factor and divide HED
by that factor
Maximum Recommended Starting
Dose (MRSD)
35. Conclusion
Whatever the strategy, it is ultimately the drug
that speaks.
A development program will typically have one or
more “champions” and several stakeholders from
numerous disciplines who may rationalize why the
drug candidate should continue along the
development path instead of intaking the difficult
decision to terminate the program.
The basic paradigm will continue to comprise
intense planning, strategic decision making,
extensive research, long term nonclinical safety,
and clinical safety and efficacy studies,
comprehensive data collection and statistical
analyses, and relevant support programs.