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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 1215 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

Targets Types Established

Subject of discovery which include proteins whose is discovered by function basic scientific research Have a detailed description of its 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 computergenerated 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

Microbial metabolites

Marine invertebrates

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.

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

Hit -Lead:
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 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

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 Genetics Molecular Biology Bioinformatics


Structure Determination X-ray Crystallography NMR Spectroscopy Computer-Aided Design Molecular Modeling Computer Graphics Biological Assays High-Throughput Screening 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
Pkinetics Tolerability Side effects in healthy individuals Is it safe ?

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?

Phase 4
Post market surveillance The drug may accepted or recalled by FDA

-- 5yrs --

- 1.7 yrs -

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

Associated members

Carried out by qualified clinical pharmacologist & trained physician Dose is given in cumulative manner to achieve the effective dose

Purpose of study

Pkinetics,Pdynamics Emphasis of safety and tolerability

Phase II :Therapeutic exploration & dose ranging May be blind or open label (4centres or more)
100-400patients or volunteers According to specific inclusion and exclusion criteria

Number of subjects

Associated members

Physicians These are trained as investigators

Purpose of study

To establish therapeutic efficacy of drug ,dosage regimen & ceiling effect in controlled settings Tolerability & pcokinetics are studied as phase I extension

Phase III :Therapeutic confirmation or comparison Done in multicentre

Number of subjects 500-3000 Associated members physicians Purpose of study To establish value of drug in relating to existing one ADRS on wide scale in which Pcokinetic 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

Proteomics Chemi-informatics