Principles of drug discovery :

by kavya lakshmi.v
(Pharmacology)

Under the guidance of :

Dr T.Vedhavathi
Mpharm ;PhD
Cmr collage of pharmacy
Principles of drug discovery
 Drug discovery
Def: The process of drug discovery involves the
identification of lead and its targets, synthesis, characterization,
screening, and assays for therapeutic efficacy of lead. Once a
compound has shown its value in in these tests, it will begin the
process of drug development prior to clinical trails.

The average time required to bring a drug

to the market range from 12–15 years at an average cost of $600–
800 million
 Stages in drug discovery
Drug discovery
Formulation
Preclinical studies
Clinical trails

Any drug development process must proceed through several stages

in order to produce a product that is safe, efficacious, and has passed
all regulatory requirements.
Process of drug discovery
 Drug development
Target :Naturally existing cellular or molecular structure
involved in the disease pathology on which the drug acts
• Subject of discovery which include
New proteins whose is discovered by
function basic scientific research
Targets
• Have a detailed description of its
Types
Established functions in normal pathology
involved in human

Target validation :Involves demonstrating that a molecular target

is critically involved in a disease process & modulation of the
target is likely to have a therapeutic effect
 Screening & design
• Screening :Investigation of a great number of compounds for a
particular problem or feature of them
Random
• Screening Non-random
Cross
• Random involves no intellectualization & assays are done with out
structural regards
• Non-random also known as targeted or focused & more narrow
approach. compounds having a vague resemblance to weakly
active compounds uncovered in a random screened

• Whether the "hits" against the chosen target will interfere with
other related targets - this is the process of cross-screening
 Techniques in screening
High through put screening
:ideal technique which
involves the molecule
finding in such a way that
hits only the chosen target
even not the related
• It is often done for a
molecule which already has
some of the desired
properties
Virtual high through put
screening : where screening
is done using computer-
generated models and
attempting to "dock" virtual
libraries to a target, are also
often used.
• This is hit-lead phase is
followed
 Approches
• Nature of sources
• Chemical sources
• Rational approches
• Molecular modelling
• Combnitorial chemistry
• Biotechnology
• Bioinformatics
• Preclinical studies
• Clinicaltrails
 Nature of source

Plant species provide a potenial source of strating or crude

material for the drug discovery

Many cardiotonics are plant derived Plant derivatives

 Microbes are the main source of antimicrobial drugs

Microbial Marine
 Streptomyces species have been a source of antibiotics. metabolites invertebrates

 Marine environments are potential sources for new

bioactive agents.

Arabinose neucleosides discovered from marine

invertebates
 • These include semisynthetic drugs
• It has organic and inorganic sources
Chemical source • Mineral resources are one of it.
• New source of chemical synthesis is
Combinatorial Chemistry

Combinatorial chemistry: involves the

synthesis or biosynthesis of chemical
libraries (a family of compounds having
a certain base chemical structure) of
molecules with in a short period of time
for the purpose of biological screening,
particularly for lead discovery or lead
modification.
 Methods
• There different types of combinatorial synthesis

 combinatorial synthesis
 Split Synthesis: Peptide Libraries
 Encoding Combinatorial Libraries
 Nonpeptide Libraries

• The main differences among the various combinatorial

approaches are the solid support used, the methods for
assembling the building blocks, the state (immobilized or in
solution) and numbers (a fraction of the total library or
individual entities)
 Rational approches
• Re-testing, dose response
curve,secondaary
Hit screening,chemical
confirmation amnebilty,biophysical
techs &hit ranking and
clustering

Hit -Lead: • Affinity, molecular weight

and lipophilicity can be
linked in single parameter
Hit expansion
such as ligand efficiency
and lipophilic efficiency to
assess drug likness

• This optimization is
accomplished through
chemical modification of
Lead
the hit structure, with
optimization
modifications chosen by
employing SAR as well
as structure-based design
 Molecular modeling
Structure Modifications to Increase Potency and the Therapeutic
Index

1 Homologation

2 Chain Branching

3 Ring-Chain Transformations

4 Bioisosterism

5 SAR by NMR/SAR by MS

6 CADD
• Homologation : prolongation of saturated carbon chain with
groups that differ by a constant unit to increase pharmacological
effect & lipophilicity

• Chain branching :this involves the side branching of alkyl groups

instead of long straight chain alkyl groups

• Ring chain transformation :effective pharmacokinetic properties

are obtained by transformation of alkyl substituent's into cyclic
analogs

• Bioisosterism :Bioisosterism is an important lead modification

approach that has been shown to be useful to attenuate toxicity or
to modify the activity of a lead
• SAR/NMR :This approach, termed SAR by
NMR, was initially used to discover
compounds with nanomolar affinitiess by
tethering two molecules with micro molar
affinities (low potency).

• CADD :Computer-aided design (CAD), also

known as computer-aided design and
drafting (CADD) , is the use
of computer technology for the process of
design and design-documentation. Computer
Aided Drafting describes the process of
drafting with a computer
 Technological Approach
Target Identification
ssssGenetics
Molecular Biology
Bioinformatics

Structure Determination
X-ray Crystallography
NMR Spectroscopy

Computer-Aided Design Biological Assays

Molecular Modeling High-Throughput Screening
Computer Graphics Computer-Based Screening

Synthetic Chemistry
Peptidomimetics
Combinatorial Chemistry

Pre-clinical Trials
 Preclinical studies
• Acute Studies :The goal is to determine toxic dose levels and
observe clinical indications of toxicity.

• Data from acute toxic studies helps determine doses for repeated dose
studies in animals and Phase I studies in humans.

• Repeated Dose Studies :These are repeated dose studies may be

referred to as sub acute, sub chronic, or chronic. The specific duration
should anticipate the length of the clinical trial that will be conducted
on the new drug. Again, two species are typically required.

• Genetic Toxicity Studies :These studies assess the likelihood that the
drug compound is mutagenic or carcinogenic.
• Reproductive Toxicity Studies : Segment I reproductive toxic
studies look at the effects of the drug on fertility. Segment II and III
studies detect effects on embryonic and post-natal development

• Carcinogenicity Studies :Carcinogenicity studies are usually

needed only for drugs intended for chronic or recurring conditions

• Toxicokinetic Studies :These are typically similar in design to

PK/ADME studies except that they use much higher dose levels.
They examine the effects of toxic doses of the drug and help estimate
the clinical margin of safety
Preclinical studies & Clinical trails
 Clinical trails

Phase 1 Phase 2 Phase 3 Phase 4

• P’kinetics • Small scale • Large scale Post market
• Tolerability trails in patients controlled
to assess surveillance
• Side effects in clinical trails
The drug may
healthy efficacy in & • Does it work in
individuals dosage double blind accepted or
• Long term trails? recalled by FDA
• Is it safe ? toxicological
studies
• Does it work?
• -- 5yrs -- • - 1.7 yrs -
• -- 3yrs ---
 Clinical trails
Phase I:No blinding screening,open label & done in single
centre

• 20-40 max 50
• Healthy volunteers
Number of subjects
• Sometimes patients are exposed to drug one
by one

• Carried out by qualified clinical

pharmacologist & trained physician
Associated members
• Dose is given in cumulative manner to
achieve the effective dose

• P’kinetics,P’dynamics
Purpose of study
• Emphasis of safety and tolerability
• Phase II :Therapeutic exploration & dose ranging
• May be blind or open label (4centre’s or more)

• 100-400patients or volunteers
Number of subjects • According to specific inclusion and exclusion
criteria

• Physicians
Associated members
• These are trained as investigators

• To establish therapeutic efficacy of drug ,dosage

regimen & ceiling effect in controlled settings
Purpose of study
• Tolerability & p’cokinetics are studied as phase I
extension
• Phase III :Therapeutic confirmation or comparison
• Done in multicentre
Number of subjects Associated members Purpose of study

• 500-3000 • physicians • To establish value of

drug in relating to
existing one
• ADR’S on wide scale
in which P’cokinetic
data may be
obtained

• Randamised double blind comparitive trails are done

• Indications are finalized & guidelines for therapeutic use are

formulated

• Submission of NDA for licensing is done who if satisfied grants

permission for marketing
Post marketing surveillance : study of uncommon or idiosyncratic ADR dose

who occur only after long term use & unsuspected drug interactions

• Patients treated in the normal course form the study population

• It includes special cases like pediatrics ,pregnant women renal & hepatic

diseased persons who are excluded in the previous stages of clinical

trails

• Modification drug delivery systems ,route of administration, fixed drug

doses ,drug combinations etc are explored here

 Novel approaches
• Micro array techniques

• Peptidomimetics

• Pharmacogenomics

• Proteomics

• Chemi-informatics
Conclusion
Queries