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 discoveryDef: 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 developmentTarget :Naturally existing cellular or molecular structure

involved in the disease pathology on which the drug acts

Targets

Types

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

New •Subject of discovery which include proteins whose is discovered by function basic scientific research

Established •Have a detailed description of its functions in normal pathology involved in human

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

Microbes are the main source of antimicrobial drugs

Streptomyces species have been a source of antibiotics.

Marine environments are potential sources for new

bioactive agents.

Arabinose neucleosides discovered from marine

invertebates

Plant derivatives

Marine inverteb

rates

Microbial

metabolites

Chemical source

• These include semisynthetic drugs• It has organic and inorganic sources• 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

Hit -Lead:

Hit confir

mation

• Re-testing, dose response curve,secondaary screening,chemical amnebilty,biophysical techs &hit ranking and clustering

Hit expansion

• Affinity, molecular weight and lipophilicity can be linked in single parameter such as ligand efficiency and lipophilic efficiency to assess drug likness

Lead optimization

• This optimization is accomplished through chemical modification of the hit structure, with modifications chosen by employing SAR as well as structure-based design

Molecular modelingStructure 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

ssss Target Identification Genetics Molecular Biology Bioinformatics

Structure Determination X-ray Crystallography NMR Spectroscopy

Computer-Aided DesignMolecular ModelingComputer Graphics

Biological AssaysHigh-Throughput ScreeningComputer-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

Phase 1• P’kinetics• Tolerability• Side effects in

healthy individuals

• Is it safe ?• -- 5yrs --

Phase 2• Small scale

trails in patients to assess efficacy in & dosage

• Long term toxicological studies

• Does it work?• -- 3yrs ---

Phase 3• Large scale

controlled clinical trails

• Does it work in double blind trails?

• - 1.7 yrs -

Phase 4

Post market surveillanceThe drug may accepted or recalled by FDA

Clinical trails

Clinical trails

Phase I:No blinding screening,open label & done in single centre

• 20-40 max 50 • Healthy volunteers• Sometimes patients are exposed to drug one

by one

Number of subjects

• Carried out by qualified clinical pharmacologist & trained physician

• Dose is given in cumulative manner to achieve the effective dose

Associated members

• P’kinetics,P’dynamics• Emphasis of safety and tolerability

Purpose of study

• Phase II :Therapeutic exploration & dose ranging• May be blind or open label (4centre’s or more)

• 100-400patients or volunteers• According to specific inclusion and exclusion

criteriaNumber of subjects

• Physicians • These are trained as investigatorsAssociated members

• To establish therapeutic efficacy of drug ,dosage regimen & ceiling effect in controlled settings

• Tolerability & p’cokinetics are studied as phase I extension

Purpose of study

• Phase III :Therapeutic confirmation or comparison • Done in multicentre

•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

Number of subjects

•500-3000

Associated members

•physicians

Purpose of study

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

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