Concepts of Drug Design

Question 1

What is drug discovery?

Answer 1

Drug discovery is the process through which potential new therapeutic entities are identified,
using a combination of various scientific models

Question 2

What is drug design?

Answer 2

This is the inventive process of finding new medications based on the knowledge of a biological target.

This is a discipline which produces biologically active molecules by chemical synthesis followed by an evaluation of effectiveness and safety with limitation of the trial-and-error approach.

Question 3

Therapeutic index is ________

Answer 3

𝐿𝐷50/𝐸𝐷50

Question 4

Briefly discuss the processes of drug discovery.

Answer 4

1. Discovery: The initial step of drug discovery involves the identification of new active compounds, often
   called ‘leads’, which are found by screening many compounds of synthetic or natural
   sources, such as plants, animals, or microorganisms for their targeted biological properties. These active compounds serve as the basis for the development of new drugs with improved efficacy and safety.
2. Optimisation: Once these leads are identified, the next step is optimisation. This step involves making chemical changes to improve the compounds based on their structure-activity relationships (SAR). These changes aim to enhance the biological effectiveness and physical properties of the compounds. For example, modifications can improve how well the compound binds to its target (pharmacophores), its interactions with the body (pharmacokinetics), and its stability during metabolism. Methods like substrate product occurrence ratio calculator (SPORCalc) help predict how compounds will behave in the body. QSAR molecular modelling tools (e.g., CoMFA, CoMSIA) provide detailed data and equations to guide these improvements.
3. Development: After their successful pharmacodynamic optimisation in clinical trials, the manufacturing process is refined to produce the drug in large quantities and prepare it in a suitable form for administration.

• Comparative molecular field analysis (CoMFA)
• Comparative
  molecular similarity index analysis (CoMSIA)

Question 5

Mention 5 sources of drug compounds/leads

Answer 5

1. Nature
2. Application of hypothesis
3. Serendipitous discovery
4. Side effects e.g. Minoxidil. an antihypertensive, now for hair loss
5. Metabolites
6. Rational drug design

Question 6

Discuss nature as a source of drug compounds.

Answer 6

1. Plant-derived bioactive metabolites: Plants have been a crucial source of bioactive metabolites, which serve as lead compounds for drug discovery. Before modern chemistry, many traditional medicines were plant-derived extracts. This has provided a rich pool of information about the therapeutic properties of different plants. Plants often produce different metabolites in various parts of the plant (roots, leaves, flowers). Examples of plant-derived leads include:
   i. Quinine from the bark of Cinchona officinalis, which gave rise to chloroquine, amodiaquine
   ii. Morphine from Papaver somniferum, which gave rise to codeine, heroine
   iii. Cocaine from Erythroxylum coca, which gave rise to lidocaine, procaine
   iv. Dicoumarol, derived from Melilotus officinalis, which gave rise to Warfarin and other anticoagulants
2. Microbial species with bioactive metabolites: Microorganisms have developed various mechanisms to compete for living space and nutrients, leading to the production of bioactive metabolites that inhibit the growth of competing species. This adaptive trait makes microbes a crucial source of antimicrobial drugs. An example is penicillin derived from Penicillium fungi.
3. Marine invertebrates: Ziconotide, derived from the cone snail is approved by the FDA to treat severe neuropathic pain. Several other marine-derived agents are now in clinical trials for indications, such as
   cancer, inflammation, and pain
4. Animals: Glandular products, hormones, enzymes, antitoxins sera etc.
5. Minerals: kaolin,
   chalk, diatomite, bentonite, talc, borax

Question 7

With the aid of an example, explain the rational drug design approach in discovering new drugs.

Answer 7

This involves tailoring the combinations to fit a treatment profile based on existing knowledge of the specific chemical responses in the
body or the target organism.
This is unlike the historical method of drug discovery by trial-and-error testing of chemical substances on cultured cells or animals and matching the apparent effects to treatments

An example of this case is the Cimetidine story:
In the 1960s, James Black, a pharmacologist, wanted to establish the existence of a second type of histamine receptor, one which didn’t respond to antihistamines and find histamine antagonists that selectively inhibited acid secretion. Black altered the structure of histamine and ended up producing an agonist, 4-methylhistamine, which stimulated acid secretion without producing any other histamine effects. This proved the existence of a second histamine receptor. With this in mind, the team set out to produce a selective H2 receptor antagonist. Initial attempts to find antagonists were challenging until a compound named burimamide showed promise. It was however, not orally active, so a new analogue, metiamide, which was orally active and ten times as potent replaced it. Clinical trials showed that metiamide was effective in healing ulcers, but the drug was discovered to cause agranulocytosis as a side effect. The team then replaced the thiourea
group in metiamide with a cyanoguanidine moiety, giving rise to Cimetidine.

Question 8

Mention 4 drugs discovered by serendipitous discovery.

Answer 8

1. Reserpine: developed as antihypertensive, now a tranquiliser
2. Acetanilide instead of naphthalene
3. Probenecid as antigout
4. Sildenafil: developed as antihypertensive, now used for ED
5. Chlorothiazide as diuretics

Question 9

Write a short note on the pro-drug approach in drug design

Answer 9

Some drugs are metabolised by the body. The substances that result
from metabolism may be inactive, or they may be similar to or different
from the original drug in therapeutic activity or toxicity. Some drugs, called pro-drugs, are administered in an inactive form, which is metabolized into an active form.
Most drugs must pass
through the liver, which is the primary site for drug metabolism. Once in the liver, enzymes convert pro-drugs to active metabolites or convert active drugs to inactive forms.
A pro-drug is a chemically modified inert precursor of the drug of interest, which when metabolised in the body,
turns into the pharmacologically active drug.
e.g. Methyldopa to methylnorepinephrine
Enalapril to Enalaprilat