1. Sachin Shinde Department of Chemistry S.M.Joshi College Hadapsar
DRUG TARGETS
Sachin Shinde
Department of Chemistry
S.M.Joshi College Hadapsar

2. Drugs target?
Drugs target is any biological system where drugs bind.
Generally, a target is a protein molecule although it could be any biological, be it nucleic acid, enzymes ,receptors ,lipid etc.
In the past, an animal model of disease could represent a target

4. Drug-Receptor Interaction
Ionic bond
H-bond
Van der Waals
Dipole-dipole /ion dipole
Van der waals
interaction
Phe
H-bond
Binding site
Ser O H
ionic
bond
Asp
CO2
Receptor

5. Hydrophobic
region O
Asp HO -

6. ENZYMES E+S ES complex E+P complex P+E
Enzymes are biocatalyst, agents that speed up biochemical processes without being consumed themselves.
Enzyme act as drug target by inhibiting their action
Enzyme inhibitors
1.Reversible/Competitive inhibitors
2. Irreversible inhibitors
3.Allosteric inhibitors
E+S ES complex
E+P complex
P+E

7. Competitive Enzyme inhibitor

8. Competitive Inhibitors

9. Increased Blood Vol. Rise in BP Kidney (Adrenal cortex)
Vasoconstriction
Na+ & water
retention
Kidney
(Adrenal cortex)

12. ACE inhibitors Captopril (Capoten) Lisinopril (Prinivil) Enalaprilat
Enalapril (Vasotec)
Fosinopril (Monopril)
Quinapril (Accupril)
Ramipril (Altace)
Enalaprilat
Enalapril

13. Anti inflammatory drugs
Aspirin, Ibuprofen,Nimesulide,Diclofenac. etc

15. Irreversible Enzyme inhibitorOH OH X O X

17. Non competitive (reversible) allosteric
(open)
ENZYME
Induced
fit
Binding site
unrecognisable
Binding site
ACTIVE SITE
(open)
ENZYME
Allosteric
site
Antagonist
drug binds reversibly to an allosteric site
Intermolecular bonds formed between drug and binding site
Induced fit alters the shape of the binding site
Binding site is distorted and is not recognised by the messenger

18. Receptors
Receptors are proteins either embedded in cell membranes or in the nuclei of cell

19. Chemical Messengers
Neurotransmitters: Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells
Hormones: Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body
Receptor
Nerve
Nucleus
Cell
Messenger
Cell
Nerve
Response

20. 5. Signal transduction Control of ion channels
Receptor protein is part of an ion channel protein complex
Receptor binds a messenger leading to an induced fit
Ion channel is opened or closed
Ion channels are specific for specific ions (Na+, Ca2+, K+, Cl-)
Activates or deactivates enzyme catalysed reactions within cell
Hydrophilic
tunnel
Cell
membrane

21. 5. Signal transduction Control of ion channels
Binding
site
Receptor
Messenger
Cell
membrane
Cell
membrane
Induced
fit
‘Gating’
(ion channel
opens)
Five glycoprotein subunits
traversing cell membrane
Cationic ion channels for K+, Na+, Ca2+
Anionic ion channels for Cl-

22. G coupled protein receptor

23. Ligands: Peptide hormones

24. Agonists

25. 10. Agonists Agonist binds reversibly to the binding site
Similar intermolecular bonds formed as to natural messenger
Induced fit alters the shape of the receptor in the same way as the normal messenger
Receptor is activated
Agonists are often similar in structure to the natural messenger E
Agonist R E
Agonist R
Agonist R
Induced fit
Signal transduction

26. Regulation of cardiac myocyte Ca2+ flux
Regulation of cardiac contractility by β-adrenergic
receptors

29. 6. Antagonists Antagonist binds reversibly to the binding siteM An An R E R
Antagonist binds reversibly to the binding site
Different induced fit means receptor is not activated
No reaction takes place on antagonist
Messenger is blocked from the binding site
Increasing the messenger concentration reverses antagonism

30. Design of Antidepressants SSRIS
citalopram (Celexa)
escitalopram (Lexapro)
fluoxetine (Prozac)
fluvoxamine (Luvox))
sertraline
Fluoxetine
Sertraline

31. Amine neurotransmitters are either degraded (metab)
or reuptaken
MAO
Mito
COMT

32. NUCLIC ACIDS AS DRUG TARGETS
DNA
RNA
We shall first consider the drugs that interact with DNA.
1.Intercalating agent
2.Alkylating agents
3.chain terminators
0ther Possible mechanisms:
Incorporation in DNA or RNA; misreading
Inhibition of DNA polymerase
Inhibit of enzymes involved in pyrimidine / purine biosynthesis

33. Intercalating drugs acting on DNA
Intercalating agents are compounds that insert themselves between the bases of the DNA
helix . This insertion causes the DNA helix to partially unwind at the site of the
intercalated molecule. This inhibits transcription, which blocks the replication process of the cell containing the DNA..
Inhibition of cell replication can lead to cell death

35. Drugs whose mode of action includes intercalation are the antimalarials quinine and chloroquine,
the anticancer agents mitoxantrone and doxorubicin, and the antibiotic proflavine.
In each of these compounds it is the flat aromatic ring system that insrts between the DNA base pairs is responsible for the intercalation.

36. Alkylation of DNA

39. Chain termination

41. Antiviral Drugs
Figure 20.16a

42. More recently, a series of other nucleoside analogues derived from these drugs and active against herpesviruses have been developed:                                                                                     

43. Role of RNA inside the Cell
According to traditional central dogma of genetics RNA is the intermediate carrier of genetic information between DNA and Protein.
DNA RNA PROTEIN
Transcription
Translation

44. Lipids
Generally drug interacting with the lipids which are located in the cell membranes.
Lipids act as drug target by disrupting the structure
Of cell membranes.
Drugs acting on cell membrane lipids Anaesthetics and some antibiotics
Action of amphotericin B (antifungal agent)
- builds tunnels through membrane and drains cell of vital ingredients and causes death. Fungi have Ergosterol as membrane lipid as compared to Cholesterol found in humans and thats the reason for some selective toxicity
Hydrophilic
Hydrophobic region

45. Polar tunnel formed
Escape route for ions

46. Thank You

47. Assigned Reading
An Introduction to Medicinal Chemistry by Graham Patrick,.
Medicinal chemistry an introduction by Gareth Thomas