DRUG DISCOVERY AND DESIGN Flashcards
improvement of lead compound
lead optimization
compound with a significant pharmacologic activity
lead
STEPS IN FINDING THE LEAD
-
Market first, science follows
➢ Search for trending diseases - A huge investment has to be made in the research and development of a new drug.
- Considerations:
➢ Economic – capable to spend money to find drug
➢ Medical
step 1: choose a disease
STEPS IN FINDING THE LEAD
- An understanding of which biomacromolecules are involved in a particular disease state is clearly important.
└ Ex. Hypertension as chosen disease - Target proteins
o Receptors (angiotensin receptor, vasopressin
receptors)
o Co-transporters – increase of blood volume
o Ion channels - vasoconstriction
step 2: choose a drug target
macromolecules that are targeted by drugs
target
STEPS IN FINDING THE LEAD
- Testing methods
- The test should be simple, quick, and relevant, as there are usually a large number of compounds to be analyzed.
-
Human testing is not possible at such an early stage
➢ In vitro test first, then in vivo
step 3: identify a bioassay
▪ no living organisms ; do not involve live animals
▪ specific tissues, cells, or enzyme are used (cultured)
in vitro
▪ use animals or human
▪ tests on animals often involve inducing a clinical condition in the animal to produce observable symptoms.
▪ are often needed to check whether drugs have the desired pharmacological activity and also to monitor their pharmacokinetic properties.
in vivo
- a compound which shows the desired pharmacological activity. ; positive in vivo test
- provides a start for the drug design and development process.
lead compound
Most biologically active natural products are ____ with quite complex structures and several chiral centers.
secondary metabolites
are formed when the biological molecules (carbohydrate, protein, lipids) were metabolites.
secondary metabolites
The study of medicines derived from natural sources is known as
pharmacognosy
- systems wherein the compounds are saved but not yet tested
- Pharmaceutical companies often screen their ____ whenever they study a new target.
compounds libraries
Ways to discover a LEAD compound:
- “Me too” and “Me Better” Drugs
➢ Many companies use ____ from their competitors as lead compounds
➢ AIM: To modify the structure sufficiently such that it avoids patent restrictions, retains activity, and, ideally, has improved therapeutic properties.
➢ Example: Captopril -
Enhancing a Side Effect
➢ Side effect of the drug could serve as clinical use
➢ Benzodioxanes (H-antagonist) – block H1 receptor
❖ Diphenhydramine (antiallergy)
❖ Tripelennamine (antiallergy)
➢ Promethazine (anesthetic agent)
➢ Chlorpromazine (tranquilizer)
exisiting drugs
Ways to discover a LEAD compound:
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
Ways to discover a LEAD compound:
- Frequently, lead compounds are found as a result of ____ (i.e. chance).
serendipity
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 ____ and
____.
isolated and purified
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.
structure determination
requires a suitable crystal of the sample
x-ray crystallography
❖ Common ; flexible and versatile
❖ used more commonly, as it can be carried out on any sample, whether it be a solid, oil, r liquid.
NMR spectroscopy
➢ relationship of how structural features of the molecule contribute to, or take away from, the **desired biologic activity **
➢ are essential in drug optimization
❖ to find analogues with better activity and
selectivity
structure activity relationship
summarizes the important binding groups (functional groups) that are required for activity, and their relative positions in space with respect to each other.
pharmacophore
