Transcript 1st and 2nd Lectures

PHL 616
Drug Discovery & Development
First and second lectures
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Drug Discovery & Development, Overview
 A drug target can be a receptor/ion channel, enzyme, hormone/factor, DNA, RNA,
nuclear receptor, or other, unidentified, biological entity
 Once drug targets are identified, they are exposed to a large number of compounds in an
in vitro or cell-based assay
 Compounds that elicit a positive response in a particular assay are called “hits.” Hits that
continue to show positive response in more complex models rise to “leads” (lead
identification)
 A selected few of the optimized leads (candidate drugs) are then advanced to preclinical
testing and clinical testing and therefore passed along to the product development staff
Drug Discovery, Definitions
 Drug
“A chemical substance of known structure, other than a nutrient or an
essential dietary ingredient, which, when administered to a living organism,
produces a biological effect”
 Drugs may be synthetic chemicals, chemicals obtained from plants,
microorganisms or animals, or products of genetic engineering
 Medicine
“A chemical preparation, which usually contains one or more drugs,
administered with the intention of producing a therapeutic effect”
 Medicines usually contain other substances (excipients, stabilisers, solvents, etc.)
besides the active drug, to make them more convenient to use
 To count as a drug, the substance must be administered as such, rather than
released by physiological mechanisms
 Many substances, such as insulin or thyroxine, are endogenous hormones but are
also drugs when they are administered intentionally
 Many drugs are not used in medicines but are nevertheless useful research tools
 The word drug is often associated with addictive, narcotic substances-an
unfortunate negative implication that tends to bias opinion against any form of
chemical therapy
Drug Discovery, Definitions
 Effects (therapeutic effects)
“The desired results of
administration of a medication”
 Side Effects (adverse effects)
“Effects that are harmful and
undesired, and that occur in
addition to the desired therapeutic
effects”
 Indications
“The reasons for administering a medication or performing a treatment”
 Contra-indications
“Factors that prevent the use of a medication or treatment (e.g., allergies)”
Drug Nomenclature
 Chemical name  represents the exact description of the drug’s chemical
composition
 Generic name (non-proprietary) 
- simpler than the chemical name and
- derived from the chemical name itself
- easier to remember
 Example 1: the chemical name 2-methyl-5-nitroimidazole-l-ethanol is condensed
to the generic name metronidazole. The word methylnitro is condensed to
metroni and dazole is due to its imidazole ring
 Example 2: Metoclopramide is the condensed form of the word
methoxychloroprocainamide: where Me is retained and th is written as t; chloro
is written as clo: and procainamide is written as pramide
 Brand or trade name (proprietary)  is developed by the company requesting
approval for the drug and identifies it as the exclusive property of that company.
 Example 1: Metrogyl® is the trade name for metronidazole.
 Example 2: Reglan® is the trade name for metoclopramide.
 Example 3: Amoxil® is the trade name for amoxycillin.
 Example 4: Celebrex® is the trade name for celecoxib.
Drug-Body Interactions
Pharmacokinetics
 Pharmacokinetics (in Greek: "pharmacon" meaning drug, and
"kinetikos" meaning putting in motion)
 The study of the movement of drugs in the body, including the
processes of absorption, distribution, localization in tissues,
biotransformation and excretion
Pharmacodynamics
 The study of the action or effects of drugs on living organisms
Pharmacokinetics
What the body does to the drug
vs
Pharmacodynamics
What the drug does to the body
Drug Sources
Many therapeutic agents originate
from natural products
 Until about 1950, when synthetic chemistry really
came into its own as a source of new drugs, most
of the pharmacopoeia consisted of natural
products, and they continue to be important drug
source, e.g. paclitaxel
 Such ready-made, highly evolved biomolecules
are supposed to have a better chance of
interacting with selected drug targets than do
random synthetic molecules
 Exploiting such compound library is seen as an
attractive strategy which has led to some
important therapeutic breakthroughs, such as:
 The anti-malarial drug artemesinin
 Immunosuppressants such as tacrolimus
[fujimycin or (FK506)]
 Paclitaxel and other recently introduced
anticancer drugs
Many therapeutic agents originate
from natural products
 In practice, the theoretical advantages of natural
products are balanced by several practical
disadvantages:
 Access to source material in remote places
can be troublesome for geographical reasons
 The continuing availability of the active
compound, if it cannot be synthesized on a
commercial basis, may be uncertain
 Purification and structure determination of
natural products is often difficult and timeconsuming
Many antibiotics originate from microorganisms
 Fosfomycin is produced by several Streptomyces species
 Cycloserine is an antibiotic produced by Streptomyces orchidaceous
 Bacitracin is a polypeptide antibiotic produced by strains of Bacillus subtilis and
Bacillus licheniformis
 Vancomycin is an antibiotic produced by Streptococcus orientalis
 Benzylpenicillin (penicillin G) is produced by Penicillium chrysogenum
 Cephalosporins were first obtained from a filamentous fungus “Cephalosporium”
 The intrinsic antimicrobial activity of natural cephalosporins is low, but the
attachment of various groups has yielded drugs of good therapeutic activity and
low toxicity
 Imipenem was discovered in 1980 via a lengthy trial-and-error search for a
more stable version of the natural product thienamycin, which is produced by
the bacterium Streptomyces cattleya. Thienamycin has antibacterial activity, but
is unstable in aqueous solution, so impractical to administer to patients
MOA of inhibitors of cell wall synthesis
Creation of a new drug
 The creation of a new drug can be divided into three main phases:
I.
Drug discovery: from therapeutic concept to molecule
II. Drug development: from molecule to registered product
III. Commercialization: from product to therapeutic application to sales
Drug Discovery & Development, Overview
 A drug target can be a receptor/ion channel, enzyme, hormone/factor, DNA, RNA,
nuclear receptor, or other, unidentified, biological entity
 Once drug targets are identified, they are exposed to a large number of compounds in an
in vitro or cell-based assay
 Compounds that elicit a positive response in a particular assay are called “hits.” Hits that
continue to show positive response in more complex models rise to “leads” (lead
identification)
 A selected few of the optimized leads (candidate drugs) are then advanced to preclinical
testing and clinical testing and therefore passed along to the product development staff
Creation of a new drug
 Before the start of any new project, the creation plan is judged by the
following criteria:
1. The drug’s scientific strength and originality
2. Development and marketing issues. For example:
i.
If the therapeutic target is an ill-defined clinical disorder, e.g., chronic
fatigue syndrome, will it be possible to measure clinical efficacy
objectively?
ii. Does the project face stiff competition from other companies working
in the same area, or from drugs already in clinical use?
iii. Is it likely that an esoteric drug delivery system will be required, and
if so, can this be developed?
iv. If the drug is successfully developed, is the expected market
sufficient to justify the cost of development?
 It is essential to keep such issues constantly under review, and to adapt the
project plan if necessary
Creation of a new drug, contd.
 As recently as 25–30 years ago in most companies, drug creation was much
more compartmentalized:
 Scientists produced molecules with interesting pharmacological properties
 Development functions were responsible for checking their safety and
turning them into registrable drugs
 The marketing department generated sales and turned them into revenues
 At the time, this worked well, and many companies prospered
 The drop-out rate was not excessive, because regulatory requirements
were less stringent
 The failures rate was not unduly expensive in terms of time and resources
lost
Creation of a new drug, contd.
 In the last two decades, biomedical science has advanced dramatically:
 Drug discovery and development have become more technology-driven
and, hence, expensive
 Regulatory requirements became much more stringent
 The competition is more intense
 With bigger teams, and more complex multidisciplinary tasks, effective
project management has become much more important than it used to be
to keep costs and delays to a minimum
 The increased amount of work being done in partnership with other
companies or with academic groups, adding the need for alliance as well
as project management
Drug discovery phase of a typical
project aimed at producing a new
synthetic drug
 Drug discovery starts with the choice of a disease
area and defining the therapeutic need that is to be
met
 It then proceeds to the identification of the
biochemical, cellular or pathophysiological
mechanism that will be targeted, and, if possible, the
identification & validation of a molecular ‘drug target’
 The next step is the identification of a lead structure
 This is followed by the design, testing and fine-tuning
of the drug molecule to the point ‘Drug candidate’
where it is deemed suitable for development