1. Target validation

2. Target validation

3. Target Validation—Overview
Knock-out/Knock-in/Gain-of-function, Transgenic Models
Pathways (Examples include the drugs acting on the cholesterol synthesis pathway)
Clinical Data
Antisense DNA/RNA and RNAi
Chemical Knock-out and Chemical Biology

8. Target Validation Methods: Pre-genomic

10. Target validation
Wann ist ein target für therapeutische Zwecke tauglich, also valid ?
Wenn es in hinreichend kausalem Zusammenhang mit der Krankheit steht:
Als Enzym, GPCR, Ionenkanal, Rezeptor usw. Überprüfung durch screening mit Leitstrukturen aus focused libraries
Als target auf DNA, RNA, mRNA Ebene selber Überprüfung durch knockout Mutationen (siehe unten), single point Mutationen (SNPs, siehe unten), und gene silencing mittels durch RNA interference (RNAi) (siehe siRNA)

11. Target validation

12. Target validation

13. Target validation

14. Human Immunodeficiency Virus(HIV)
Human Immunodeficiency Virus(HIV). The outer shell of the virus is known as the Viral enevlope.
Embedded in the viral envelope is a complex protein known as env which consists of an outer protruding cap glycoprotein (gp) 120,
and a stem gp 41.
Within the viral envelope is an HIV protein called p17 (matrix),
and within this is the viral core or capsid, which is made of another viral protein p24 (core antigen).

15. STRUCTURE OF HIV-1 VIRUS
envelope
glycoproteins
dřeňové
proteiny
Gp120 (cap)
Gp41 (Stem)
P17(matrix)
P24 capsid(core antigen)
core
proteins p9
lipidic
bilayer
p32
reverse
transkriptase
(p66)
RNA

16. Target validation

17. Target validation

18. HIV-1 HOST CELL INTERACTION
IST initiation
IIND adsorption
IIIRD penetration
gp41
gp120
gp41
binding-
site for
CD4
molecule
viral
RNA
gp120
V3loop V1 V3
V3loop V2
CCR5
CD4 V3
CD4
CCR-5 V4

19. Target validation

20. Target validation

21. Prediction is very difficult, especially about the
future (Niels Bohr, also attributed to Mark Twain)
"Everything that can be invented has been invented."
Charles H. Duell, U.S. Office of Patents, 1899.
"I think there is a world market for maybe five
computers." Thomas Watson, Chairman IBM, 1943
"Computers in the future may weigh no more than
1.5 tons." Popular Mechanics, forecasting the relentless
march of science, 1949
"There is no reason anyone would want a computer in
their home." Ken Olson, President, Chairman and
Founder of Digital Equipment Corp., 1977
"640 k ought to be enough for anybody."
Bill Gates, Founder of Microsoft, 1981

22. Important Mispredictions in Drug Therapy
There is no market for cyclosporin, because there
are too few organ transplants.
The breakthrough in transplantation medicine was
enabled by cyclosporin.
There is no market for Cimetidin. Gastric and duodenal ulcera can be treated conventionelly (by surgery!)
In 1983, six years after its market introduction, cimetidin had yearly sales of one billion US-$.
Omeprazole will „dry out“ the stomach, because of its complete blockade of gastric acid production.
Omeprazole developed to the most successful drug of all time (more than six billions US-$/year).