1. Rational Drug Design and Drug action
Chapter- 2
Rational Drug Design and Drug action
DR. Ghulam Abbas

2. Rational Drug Design
Introduction
Drug: Compounds used for the prevention and treatment of diseases like cancer, etc.
Ideal drug: Ideal drugs are the drugs which have the following properties;
1) Targeting the bio-molecule which are involved in signaling or metabolic pathways, that are specific to disease process by either protein-protein or protein-nucleic acid interactions.
2) antagonist action-inhibiting functions of the disease causing proteins.
3) Inhibiting interactions of the proteins.
4) Activates other proteins, that are deregulated in such disease like cancer.

3. Rational Drug Design Drug designing is; 1) Challenging 2) Expensive
3) Time consuming
So, Multidisciplinary approach such as, Computational tools, methodologies for structure guided approach + Global gene expression data analysis by softwares are used.
Hence,
Efficiency increased
Cost effectiveness
Time saved
Strategies to overcome toxic side effects

4. Drug Design
2 ways:
Development of ligands with desired properties for targets having known structure and functions.
Development of ligands with predefined properties for targets whose structural information may be or may not be known.
This, unknown target information can be found by global gene expression data.

5. Figure 1: Possible steps in drug designing for known target

6. Figure 2: Possible steps in drug designing for unknown target
Homology= Similarity of structure or function of parts of different origins.
Figure 2: Possible steps in drug designing for unknown target

7. Additional properties towards the improvement of drug like properties Figure 3:
QSAR= Quantitative –SAR models
QSPR= Quantitative –S-Property R models
Figure 3: Additional properties towards the improvement of drug like properties

8. Combination Therapy
Ancient Asian herbal medicine with combination of many herbs produced no side effects
Same approach is applied to modern medicine
We can use combination of different drugs to combat a specific disease like cancer.

9. Drugs and Drug Action
Definition – Drugs
It is defined as the chemicals (not light, sound, radiation, magnetic field) which prevent from diseases or assist in restoring health
History
Drugs originated from natural products
Examples include opium, belladonna, cinchona, marijuana, digitalis, quinine, ………….
First use of synthetic organics …… ether and chloroform for anesthesia in 1830s
Structural derivatives …

10. Drugs and Drug Action Why do drugs work?
‘the hydrophobic effect?’ …. Lipophilicity was thought to be important
‘the medium effect?’ … generally changed conditions
‘the receptor effect?’ … Langley and Ehrlich’s hypothesis (1905)
The Receptor Hypothesis
Certain cells contain receptive substances that served as hosts for the drug molecules to bind
Example: pilocarpine was selective and potent for excitation of parasympathetic nervous system, while atropine was capable of blocking this effect! …… both interact with same component of the cell.

11. ‘receptive’ substance  ‘receptor’
A macromolecule that recognizes ‘drugs’ through precise physicochemical and steric interactions.
Receptor
Most drugs work through a receptor
e.g., testosterone or steroidal sex hormones; calcium channel blockers; growth factors; etc.
Few drugs work without a receptor being involved
e.g., EDTA (for removing lead poisoning from bloodstream); Mg(OH)2 for gastric acidity; mannitol for diuretic; etc.
Drug targets
Cellular receptors (52%)
Enzymes (28%)
Hormones and factors (11%)
DNA (2%)
Unknown (7%)

12. Theory of Drug Action
Koshland’s ‘Induced-Fit’ Hypothesis
At least two steps …… e.g., step 1 is initial binding and step 2 is a change in structure of the receptor (and/or drug)
Receptor is flexible! …… can wrap around the drug …… the zipper model is extreme case of induced-fit
All intermediate cases do exist in nature

13. Every ‘lock’ has its own ‘key’
Theory of Drug Action
Fischer’s ‘Lock and Key’ Hypothesis
Every ‘lock’ has its own ‘key’
If the ‘key’ is not precise, the ‘lock’ does not open
The ‘drug’ is the key that has to fit the target specifically and productively

14. Theory of Drug Action
Corollary of ‘Lock & Key’ Hypothesis
Does not explain why some ‘keys’ open doors partially? …… e.g., partial agonists or antagonists

15. Drug Action
The chemical in a drug combines with or alters the molecules in body cells so that it changes the way the cells work.
The 4 main drug actions are:
1. Depressing
2. Stimulating
3. Destroying cells
4. Replacing substances

16. Drug Action
Drugs usually speed up or slow down the ordinary processes the cells carry out
Example: antihistamines slow the body’s natural reactions to irritation, and stimulants speed up the energy-producing functions of cells

17. Drug Action Some drugs destroy certain cells or parts of cells
Example: antibiotics kill disease microorganisms; 5- Fluorouracil (5FU) and methotrexate kill cancer cells.
Some drugs action is to replace or supplement natural substances that the body lacks due to organ malfunction or poor nutrition
Example: Potassium chloride and calcium carbonate

18. 4 Basic Body Processes That Affect Drug Action
Absorption
Distribution
Metabolism/Biotransformation
Excretion

19. Absorption
Absorption is the passage of a drug from the site of administration into the bloodstream
How quickly a drug is absorbed is important because it determines how soon it will start it’s action
The route of administration can affect the rate of absorption

20. Absorption Route of Administration Sublingual (under tongue)
Oral( by mouth)
Subcutaneous
Intramuscular
Intravenous
Absorption begins
In the mouth
In the stomach/intestine
Under the skin
In the muscle
In the blood stream

21. Distribution
Distribution is the transport of the drug from the bloodstream to the body tissues and intended site of action
Some of the drug passes through the capillaries thin walls (alcohol passes easily thru capillaries and into tissues quickly)
Distribution time varies with different drugs

22. Metabolism/Biotransformation
This is a series of chemical reactions that inactivate a drug by converting it into a water-soluable compound so it can be excreted by the body
Sort of like digesting food, the body uses enzymes to break down the drug and detoxify toxic substances
The liver is where most metabolism takes place , some occurs in the lungs, intestines, kidneys, & blood

23. Excretion Excretion is the body’s way of removing the waste products.
Most drugs leave the body through the kidneys and large intestine
The lungs, sweat, hair, and milk glands also excrete
An elderly person with kidney disease has an increased risk of toxicity….WHY?

24. Patient Education Concerning Excretion
Increase fluid intake to aid in excretion
Cough & deep breathe after anesthesia
Chew gum or hard candy to decrease
Avoid laxatives, they speed up drug excretion
Keep skin clean to avoid irritation from excretion (sweat)
Unpleasant taste from excretion via saliva
Improper diet & lack of activity slow excretion
Pregnant or nursing moms should check with MD

25. Factors Affecting Drug Action

26. AGE Infants body systems are immature
The body systems of the elderly may have decreases in kidney and liver function
Smaller doses may be required to treat the young and old

27. SIZE
The average adult dose is calculated for a person age weighing 150lbs
As a result, doses for the young, elderly, or obese must be calculated by body weight

28. DIET Combining certain foods with certain drugs can alter the effects
EX: Tetracycline/Milk
Coumadin/Vitamin K

29. SEX Women are generally smaller than men and have more body fat
Pregnant women must always consult their physician because of a drugs risk to the fetus

30. GENETIC FACTORS
Heredity can affect a persons metabolism and excretion process
Some people lack the naturally occurring enzymes to break down drugs for excretion

31. PATHOLOGICAL CONDITIONS
Diseases can strongly affect how patients respond to drugs
Heart disease, kidney failure, diabetes, and low blood pressure can affect drug action
Cancer can also affect drug action, requiring a stronger dose

32. PSYCHOLOGICAL FACTORS
A positive attitude is likely to respond well to medication
Some patients have taken a placebo and reported feeling better
Strong feelings such as worry, anger, fear or jealousy can affect drug action

33. ROUTE OF ADMINISTRATION
A drug acts more quickly when injected directly into the bloodstream
Medications taken by mouth take the longest time to show effects

34. TIME OF ADMINISTRATION
Important to give meds at time they were ordered
Some drugs need to be taken with a meal, others are absorbed more quickly on an empty stomach

35. DRUG-TAKING HISTORY
A patient can build up a tolerance to a particular drug
Some drugs can interact with each other
Always check allergies

36. ENVIRONMENTAL CONDITIONS
Heat and cold can affect drug action
Heat relaxes the blood vessels, speeds up circulation, drugs act faster
Cold slows action by constricting vessels

37. DRUG EFFECTS

38. Drug Effects Therapeutic effect – what you want
Side effect – what you may get along with the therapeutic effect (some good, some bad)
Ex: Morphine – therapeutic effect – kills pain, side effect – respiratory depression/constipation/urine retention

39. Classification of Drug Effects
Local – affects mainly the area it enters or is applied. Benadryl ointment applied to a bug bite on skin.
Systemic – travel throughout bloodstream to affect cells or tissues. Benadryl capsule taken by mouth due to allergic rash.

40. Adverse Reactions What you don’t want!!!
Idiosyncrasy – opposite of expected effect
Tolerance – lessened effect
Cumulation – stronger effect
Toxicity – different symptoms affecting organs
Synergism – stronger effect when more than one drug taken

41. Adverse Reactions
Antagonism – weaker effect when more than one drug taken (tetracycline & antacid)
Potentiation – effect of one drug increases effect of another drug (tylenol & codeine)
Interaction – therapeutic or adverse effect on body
Physical dependence – physical need for a drug
Psychological dependence – mental craving for drug