Stages in drug discovery & drug development (4- Lead Modification and…
Stages in drug discovery & drug development
1- Choosing a disease
2- Choosing a drug target
e.g. receptor, enzyme, a nucleic acid, ion channel).
7- Pre-clinical testing ( pharmacological and toxicity testing
1) to examine any effects on cell reproduction
2) & to identify potential carcinogens.
starts with in-vitro and in-vivo testing on genetically engineered cell cultures or transgenic mice
3- Finding a lead compound :
:check: first drug (proto-type) in the class
:check:shows desired pharmaceutical activity.
:check:The level of activity may not be very great and there may be undesirable side effects
:check:provides a start for drug development process (Me TOO drug).
1-Hydrogen bond donors
2-Hydrogen bond acceptors
3-Positive Charge Centers
4-Aromatic ring centers
:check:should be acc with :
1) Isolation or synthesis, purification,
2) structure determination through spectral data and/or X-ray crystallography
sources of lead compound :question:
d) Computer-aided drug design
Molecular modeling software programs used to :
design molecules which will fit and bind
study the binding site,
a) Natural sources
ex : morphine (lead compound ) , Mepridine (Pethidine) (Me TOO drug) , Methadone (Me TOO drug)
M.O such as fungi has provided penicillin G as a lead compound , amoxicilin ( Me TOO drug )
(by luck )
! anti-impotence drug viagra was discovered during the developing of a new heart drug.
cisplatin, penicillin, nitrogen mustard….etc
: ex adrenaline and noradrenaline were the starting points for the development of adrenergic beta-agonist such as
Me Too drugs
chemically related to the prototype, or other chemical compounds which have an identical mechanism of action
shows some desired pharmaceutical activity
not be used as therapeutic agent.
starting point for developing a lead compound
4- Lead Modification and optimization (Improvement of drug target interactions and the pharmacokinetic properties of the drug).
To provide easy and efficient administration to the patients
To reduce the side effects
To increase the activity
To increase the selectivity
To produce easily synthesized drugs
Variation & positional change of substituents
Extension of the structure
Rigidification or Simplification of the structure
Ring expansions or contractions
Replacement of an atom or group of atoms in a (lead) drug by another atom or group of atoms that is similar in electronic and steric configuration with or without significant change in the proper biological activity of the drug.
ex e.g. Replacement of –O- of procaine by –NH- in procainamide leads to prolong local anesthetic effect.
5- Identification of structure activity relationships and the pharmacophore
The relevant groups on a molecule that interact with a receptor and are responsible for activity
6- Studying drug metabolism
9- Clinical trials and drug Marketing :There are 4 phases of clinical trials
Phase IV: the drug is now placed on the market and can be prescribed. However, the drug is still monitored for its effectiveness and for any unexpected side effects
Phase II: the drug is tested on a small group of patients
Phase III: the drug is tested on a large group of patients.
Phase I: the drug is tested on healthy volunteers
8) Manufacturing the drug on large scale :check:
economic, safety issues become far more important.