Advaces in cell biology: contribution to drug modern design

1. ADVANCES IN CELL BIOLOGY:ADVANCES IN CELL BIOLOGY:
CONTRIBUTIONS TO MODERN DRUGCONTRIBUTIONS TO MODERN DRUG
DESIGNDESIGN
Esayas Ayele
Department of Pharmaceutics and
Social Pharmacy

2. Outline
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 Introduction
 Cell biology in drug design
 Proteins
 Genomics
 Proteomics
 Nucleic Acid as drug target
 Membrane as drug target
 Summary

3. Introduction
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 What is cell?
 The cell is the basic structural, functional, and
biological unit of all known living organisms.

4. Introduction…
 Cell biology is a branch of biology that studies the
different structures and functions of the cell.
 Structure
 Organelles
 Physiological properties
 Metabolic processes
 Signaling pathways
 Life cycle
 Interactions with their environment.
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5. Introduction…
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Fig 1. Prokaryotic Vs Eukaryotic Cell

6. 6
Fig 2. Structure of Animal Cells

7.  Growth and
development
 cell cycle
 Transport across cell
membrane
 Autophagy
 Adhesion
 Cell movement
 Cell signaling
 DNA repair
 Metabolism
 Transcription and
mRNA splicing
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Processes

8. Cell Biology in Drug Design
 Cell biology is a major driver of all aspects of biomedicine.
 The diagnosis of a disease increasingly relies on genetic,
molecular, and cellular markers, and
 Drug discovery has shifted from blind screening to targeted
molecular design informed by our genetic, molecular, and
cellular understanding of a disease.
 Identifying and characterization of therapeutic target
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9. Proteins
 Enzymes
 Receptors
 Membrane Transport Proteins
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10. G Protein-Coupled Receptors
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11. GPCRs…
 Drug discovery programs of many pharmaceutical
companies focus on the G-Protein Coupled Receptor
(GPCR) superfamily.
 In many diseases GPCRs are known as ‘‘validated
targets’’, i.e. ligands acting at the GPCR are known to
affect the disease outcome in human.
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12. GPCRs…
 Bioinformatic analysis of the human genome sequence
has revealed several hundred new members of the GPCR
family.
 As GPCRs are one of the most important families of
targets in drug discovery in the pharmaceutical industry, it
is
expected that the various newly identified receptors offer
similar potential and will also prove to be good drug
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13. GPCRs as a drug target
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14. Orphan GPCRs
 Attempts have been made to deorphanise these receptors
 Ligand Hunting:
 Reverse Pharmacology Approaches to oGPCRs
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15. Deorphanised GPCRs reported to be in drug discovery
British Journal of Pharmacology (2008) 153 S339–S346
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16. Proteins...
Enzymes
 obvioustarget for therapeutic intervention when adisease
stateisassociated with production of a bio lo gically active
species.
e.g. DHFR vs. Methotrexate, ACE vs. captopril
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17. Nucleic acid as drug targets
 DNA
 asthereceptor for many drugsused in cancerand other diseases;
 usesto design sequence-specific reagentsfor genetherapy.
 e.g. chemical modification and crosslinking of DNA (cisplatin)
or cleavageof theDNA (bleomycin)
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18. Nucleic acid as drug targets
 RNA as drug target
 Drugs that bind to RNA might produce effects that cannot be
achieved by drugs that bind to proteins.
 e.g. Aminoglycosides and macrolides are RNA-targeting
antibiotics that inhibit prokaryotic translation
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19. Membranes as drug targets
 An understanding of the structural and dynamic functions
of the membranes may add to a more rational design of
drug molecules with improved permeation characteristics
or specific membrane effects.
 E.g. Amphotericin B
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20. GenomicsGenomics
 Structural genomics — the sequence
 Information is encoded linearly and digitally in four
coding molecules-bases
 Three bases = codon = amino acid
 A number of codons strung together code for a gene
which codes for a protein
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21. Genomics…
 Functional genomics — what the genes
do
 Sequence/structural motifs in proteins i.e.
functional class of protein
 Microarrays of gene expression
 Proteomics
 Pharmacogenomics
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22. Functional Genomics: Microarrays of Gene
Expression
Normal tissue
DNA
Diseased
Diseased
associated
normal
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23. GenomicsGenomics
 From the Human Genome to New Drugs
 Human Genome Project and
Celera
 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.
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24. Proteomics
 “Proteome”-the protein complement encoded by a genome
 Proteomics is the study of composition, structure, function
and interaction of the proteins directing the activities of
each living cell
 Identification of the precise 3D-structure of relevant proteins to
enable researchers to identify potential drug targets to turn
protein “on or off”
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25. Why Proteomics
 Beyond the genetic make-up of an individual or organism, many other
factors determine gene and ultimately protein expression and therefore
affect proteins directly such as pH, hypoxia, drug treatment…
 Proteins can undergo extensive modifications such as glycosylation,
acetylation, and phosphorylation which can lead to multiple protein products
from the same gene
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26. Proteomics…
The level of any protein in the cell at any given
time is controlled by
1. Rate of transcription of the gene
2. The efficiency of translation of m RNA into
protein
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27.  Gel Electrophoresis
 Mass Spectrometry
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Proteomics Tools

28. Determining the protein structure/polypeptide sequence
1. x-ray crystallography
2. Nuclear magnetic resonance
3. Protein predicting programmes- computer based
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29. Proteomic Bioinformatics
 Databases exist for the protein maps of a broad range of organisms,
tissues, and disease states
 Ultimately, given the the dynamic nature of the proteome, complex
experimental details and related results need to be extrapolated in the
context of the relevant biochemical pathways or disease implications
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30. Databases
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31.  Genome and proteome informations are used to
identify the proteins associated with the disease.
 That protein will be used by computer software as a
target for new drug.
 HIV-1 Protease
Proteomics and drug discovery
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32. Summary
 Theintroduction of genomics, proteomicsand metabolomicshaspaved theway
for biology-driven process, leading to plethoraof drug targets.
 Today, biomedicinesitson thecusp of anew revolution: theuseof microbial and
human cellsasversatiletherapeutic engines
 Today, biomedical sciencestandspoised at thethreshold of another
pharmaceutical frontier: cell-based therapies. 32

33. References
 Olivera, B.M., 1997. EE Just lecture, 1996 Conus venom peptides, receptor and ion channel
targets, and drug design: 50 million years of neuropharmacology. Mo le cular bio lo g y o f the ce ll,
8 (11), pp.2101-2109.
 Goldgur, Y., Craigie, R., Cohen, G.H., Fujiwara, T., Yoshinaga, T., Fujishita, T., Sugimoto, H.,
Endo, T., Murai, H. and Davies, D.R., 1999. Structure of the HIV-1 integrase catalytic domain
complexed with an inhibitor: a platform for antiviral drug design. Pro ce e ding s o f the Natio nal
Acade m y o f Scie nce s , 9 6 (23), pp.13040-13043.
 Butcher, E.C., 2005. Can cell systems biology rescue drug discovery?. Nature Re vie ws Drug
Disco ve ry, 4(6), pp.461-467.
 Butcher, E.C., Berg, E.L. and Kunkel, E.J., 2004. Systems biology in drug discovery. Nature
bio te chno lo g y, 22(10), pp.1253-1259.
 Klabunde, T. and Hessler, G., 2002. Drug design strategies for targeting G‐protein‐coupled
receptors. Che m bio che m , 3(10), pp.928-944.
 Rosenbaum, D.M., Rasmussen, S.G. and Kobilka, B.K., 2009. The structure and function of G-
protein-coupled receptors. Nature , 459 (7245), pp.356-363.
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Thank
you!