1
Q
Compound of significant pharmacological activity [API] - need makuha yung desirable effect but not always
A
- Finding the Lead
2
Q
6 parts in Finding the Lead
A
- Choose a disease
- Choose a drug target
- Identify a bioassay
- Find[identify] a ‘lead compound’
- Isolate and purify the lead compound if necessary
- Determine the structure of the lead compound if necessary
2
Q
Ways to discover a LEAD compound:
A
1.Natural Products Screening
2. Medical Folklore
3. Screening Synthetic Compound Libraries
3
Q
Ancient people used ——- products as drugs - however, many of the products were very ——–
A
natural toxic
4
Q
banned in Paris on 1566
A
Tartar emetic
5
Q
The search to find less toxic substances than those based on natural sources resulted in the introduction of synthetic substances as drugs
A
LEADS API
6
Q
Compound of significant pharmacological activity [API] - need makuha yung desirable effect but not always
A
Finding the Lead
7
Q
Market first then science follows
A
- Choose a disease
8
Q
- A huge investment has to be made in the research and development of a new drug
A
- Choose a disease
9
Q
- Choose a disease
Considerations:
A
- Economic – kikita k aba sa paggawa ng drugs na ito
- Medical – if you know the disease ano yung gamot for it [therapeutic use]
10
Q
- You know the target you will know the applicable medication
A
- Choose a drug target
11
Q
- An understanding of which biomacromolecules are involved in a particular disease state is clearly important.
A
- Choose a drug target
12
Q
- The test should be simple, quick, and relevant, as there are usually a large number of compounds to be analyzed.
A
- Identify a bioassay
13
Q
- Human testing is not possible at such an early stage
A
- Identify a bioassay
14
Q
do not involve live animals
A
In vitro Tests
15
Q
specific tissues, cells, or enzymes are used
A
In vitro Tests
16
Q
Often needed to check whether drugs have the desired pharmacological activity and also to monitor their pharmacokinetic properties.
A
In vivo tests
17
Q
On animals often involve inducing a clinical condition in the animal to produce observable symptoms
A
In vivo tests
18
Q
- Lead compound is a compound which shows the desired pharmacological activity
o Leads - has desirable effect - has undesirable effect
- The lead compound provides a start for the drug design and development process.
A
- Find[identify] a ‘lead compound’
19
Q
o Most biologically active natural products are secondary metabolites with quite complex structures and several chiral centers
A
- Natural Products Screening
20
Q
o The study of medicines derived from natural sources is known as
A
pharmacognosy in Natural Products Screening
21
Q
pharmacognosy sources
A
- Plants
- Microorganisms [antibiotic ex penicillin and cephalosporin]
- Marine life [aquatic samples ex tilapia can rejuvenate your skin]
- Animals
- Venoms and toxins.
22
Q
o Traditional/folkloric claims [medical herms to explore as therapeutic use]
A
- Medical Folklore
23
Q
o Companies will research further/explore the mini research of a person kasi sila maybadget
A
- Screening Synthetic Compound Libraries
24
o Pharmaceutical companies often try to diversify their range of structures by purchasing novel compounds prepared by research groups elsewhere.
3. Screening Synthetic Compound Libraries
25
o Pharmaceutical companies often screen their library of compounds whenever they study a new target.
3. Screening Synthetic Compound Libraries
26
"Me too" and "Me Better" Drugs
4. Existing Drugs
27
Revise the compound to make it better
4. Existing Drugs
28
Many companies use established drugs from their competitors as lead compounds
4. Existing Drugs
29
- AIM: To modify the structure sufficiently such that it avoids patent restrictions, retains activity, and, ideally, has improved therapeutic properties.
4. Existing Drugs
30
Captopril is example in ------- then explain
Existing Drugs
* Captopril has incompatibilities that cause GI disturbance/ irritation in stomach lining
* So kung maiimprove at matatangal ang GI disturbance na ito the drug will become much better
* Walang nalalabag na law/ or copy right
31
Benzodioxanes is example in ------- then explain
Benzodioxanes major action is on the nervous system but it can also inhibit histamine receptor [having effect on the histamine1 receptor that will effect as anti-allergy] that will produce Ethanolamine, and from Ethanolamine na produce si Ethylenediamines [effect ay anti-allergy]
They modify the stracture of Ethanolamine that came from Benzodioxanes to produce Diphenhydramine there for na produce yung anti-allergy therefore it will prevent the production of histamine/ prevent allergic reaction
Produce and revise result in the Ethylenediamines then produce Tripelennamine use as anti-allergy it is same function but different drug
But the 2 drug has side effect which is drowsiness which is not good but you can use a therapeutic use for sleeping which is anesthetic
From that you can produce Promethazine [anesthetic agent] then revise and produce Chlorpromazine [Tranquilizer]
32
o Molecular modelling software programs can be used to study the binding site and to design molecules which will fit and bind to the site (de novo drug design)
Computer-aided Design
33
o binding site is important para doon magfit yung substate + active site = enzyme
o need ng courses of attraction in the binding side [so need iidentify yung binding site]
Computer-aided Design
34
define different bonding
1. Ionic Bond – opposite charge / nitrogen
2. Hydrogen Bond - OH group
3. Van der waals – Carbon / non-polar
35
o Accidental drugs discovery / chance discovery
- Ex. Penicillin
Serendipity
36
o Frequently, lead compounds are found as a result of serendipity (i.e. chance).
Serendipity
37
* Isolated and purified which of those components would be your API
Isolate and purify the lead compound if necessary
38
* If the lead compound (or active principle) Is present in a mixture of compounds from a natural source or a combinatorial synthesis, it has to be isolated and purified because you need to remove the toxic substance to pure substance.
Isolate and purify the lead compound if necessary
39
* Structure determination is a relatively straightforward process and it is only when the natural product is obtained in minute quantities that a full synthesis is required to establish its structure.
Determine the structure of the lead compound if necessary
40
– NEED TO TRANSFOR INTO CRYSTALINE FORM
o requires & suitable crystal of the sample
X-ray crystallography
Determine the structure of the lead compound if necessary
41
– BEST USE
o used more commonly in the Philippines, as it can be carried out on any sample, whether it be a solid, oil, or liquid.
NMR spectroscopy
Determine the structure of the lead compound if necessary
42
raw materials guaranty to have a desirable effect and there properties to be modify therefore in modification of the compound trying to the drug designing.
Drug Design
43
METHODS Drug Design
1. Identify structure-activity relationships (SARS)
2. Identify the pharmacophore
3. Improve target interactions (pharmacodynamics)
4. Improve pharmacokinetic properties
44
* relationship of how structural features of the molecule contribute to, or take away from, the desired biologic activity
1) Structure Activity Relationship (SAR)
45
* Kailangan mag fit ng neurotransmitter doon sa binding site that will apply the ----
* So dapat mag fit yung structure ng gamot mo and yung structure ng target mo
1) Structure Activity Relationship (SAR)
46
* AIMS of this is to Identify those part of the molecule that are importance in the biological activity and those are not active [titignan kung ano yung magkakaroon ng activity and non activity]
1) Structure Activity Relationship (SAR)
47
* SAR Studies are essential in -------
drug optimization
48
2 SAR Studies are essential in drug optimization
o to find analogues with better activity and selectivity
o remember Pharmacodynamics – powerful and selective enough
49
* summarizes the important binding groups that are required for activity, and their relative positions in space with respect to each other.
* Not modify as it is na yun
2) Pharmacophore
50
* Pharmacodynamics optimization
* Pharmacokinetic optimization
* We want to enhance the intramolecular bonds within the target in order for a drug to powerful and selective enough
3) Drug Optimization
51
Explain Drug development
Drug discovery, Drug design, Drug trials [phase1,2,3,4] , Drug manufacturing/process
PHARMACOLOGY
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