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HERBAL AND DRUG DESIGN TECHNOLOGY Selma Siyavudeen

Introduction To Drug Discovery

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an introduction to drug discovery

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Page 1: Introduction To Drug Discovery

HERBAL AND DRUG DESIGN TECHNOLOGY

Selma Siyavudeen

Page 2: Introduction To Drug Discovery

(IUPAC Recommendations 1997)

Drug designDrug design includes not only ligand design, but also pharmacokinetics and toxicity, which are mostly beyond the possibilities of structure- and/or computer-aided design.

Drug design is most often used instead of the correct term "Ligand Design”.

Page 3: Introduction To Drug Discovery

The process of drug discovery

Primary requirement - Target identification

The disease against which a drug has to be developed .

New drug research starts with an understanding of how the body functions, both normally and abnormally, at its most basic levels.

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Drug discovery / design - steps

IDENTIFICATION

OPTIMISATION

DEVELOPMENT

FINDING A LEAD COMPOUND / NCE

QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS,ASSAYS – in vitro and in vivo

PHARMACOKINETIC STUDIESTOXICOLOGY TESTING

FORMULATION DEVELOPMENTCLINICAL TRIALS

REGULATORY APPROVAL

LEAD

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Drug design (ligand design)

STEP 1

LEAD IDENTIFICATION

Find a lead compound /NCE (New Chemical Entity)

This is usuallyis usually a molecule with demonstrable but weak activity of the desired type

.

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sources of lead compounds

Random screening -plants, animal, microbial & synthetic sources

Observed side effects of known drugs

eg. oral antidiabetic agent tolbutamide was discovered by the careful molecular modification of a sulfa drug which showed lowering of blood glucose as a side effect.(Grunwald 1970).

Page 7: Introduction To Drug Discovery

Natural products of known pharmacological properties eg. the structure of the natural anticoagulant, bishydroxycoumarin, led to the synthesis of a distant analogue the widely used anticoagulant drug warfarin

structure of natural body substances. enzyme inhibitors are often designed from the structure of

substrates. eg. The monoamine oxidase inhibitor pargyline is an analogue of the substrate,benzyl amine.(Martin et al,1975)

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Insilico approach/computer assisted drug design (CADD)

Based on ligand receptor binding

Ligand based or receptor based designs

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An Example of CADD: Carbonic anhydrase

CO2+H2OHCO3 + H+

the hydration of some aldehydes and ketones, and the hydrolysis of alkyl and aryl esters.

Inhibitors include aromatic and heterocyclic sulfonamides

(MTS [(4S-trans)-4-(methylamino)-5,6-dihydro-6-methyl-4H-thieno (2,3-B)thiopyran-2-sulfonamide-7,7-dioxide

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engage in a greater number of favorable interactions within the large carbonic anhydrase active site than can the smaller arylsulfonamides.

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CADD Advantages & Limitations

flexible, faster docking techniques, virtual screening and library design.

identifying potential drugs than

may be considerably different from existing drugs.

reduced reagent storage and handling of large libraries

optimum fit in a target site does not guarantee that the desired activity of the drug will be enhanced or that undesired side effects will be diminished.

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STEP IILEAD OPTIMISATION

synthesize and test an exploratory series if analogues of the lead.

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Synthesis of homologues and analogues from a prototype

Method of variaton Tool for design of new drugs in a rational fashion, having more desirable properties and advantages than the prototype.

Variation through disjunction or conjunction

Objectives Include the design of agents with improved Potency Specificity Duration of action Ease of administration and handling Stability Cost of Production

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design of variants

Familiarize thoroughly with the prototype

From the molecular structure information can be drawn about The nature of chief chemical classes to which the product

belongs as determined by the main stem nuclei or the hydrocarbon skeleton from which it derives its name

The nature and number of various functional groups their positions and their proximity with respect to one another.

The various possible degrees of rotations and extension of the structure in to various possible configurations.

The likelihood of steric hindrance between various portions of the molecule in different configurations in space

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QSAR

Formulate a preliminary quantitative structure- activity relationship (QSAR) and designs further analogues to test and expand the relationship.

attempt to correlate structural or property descriptors of compounds with activities

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QSAR

parameters to account for hydrophobicity, topology, electronic properties, steric effects,

determined Empirically statistical analysis, computational methods.

chemical measurements and biological assays.

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Step iiiLead Development

Preclinical testing

Clinical trials

Pharmacovigilance

Toxicology Pharmacokinetics/ADME Preformulation Formulation

Phase I,ii,iii,iv

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Animal pharmacokinetic studies

ADME Studies using radioactive versions of NCE

Absorption Distribution Metabolism Excretion

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Safety pharmacology Genotoxicity – gene mutations Acute toxicity testing Repeat toxicity testing Reproductive toxicology carcinogenicity

Toxicity testing

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Formulation development

Preformulation involves Solubility determination pKa determination Partition coefficient Chemical stability profile Particle size, shape and

surface area

Formulations should be Stable Easy to administer Easy and economic to

manufacture East to transport and store

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Clinical trials

Page 22: Introduction To Drug Discovery

REVOLUTIONS IN DRUG DESIGN technology

Advances in molecular biology , Genomics Microarray technology Development of high throughput screening Advances in computer assisted molecular design

(CADD & CASE)

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Advances in molecular biology-newer targets for drugs

Identification of physiologically relevent molecular targets

determination and implementation of appropriate screening assays

Development of drugs with new pharmacological mode of action

HMG Co A reductase inhibitors - new drug target for reducing cholesterol levels

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Advances in recombinant DNA technology - biopharmaceuticals

Blood products Clotting factors Anticoagulants Thrombolytic agents Recombinant vaccines

Haemopoetic growth factors

Interferons Interleukins Monoclonal antibody

based products

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Advances in genomics & Microarray Technology

Microarray type Breif description

Applications

Expression analysis Analysis of gene expression levels

Drug development

Drug response

Tracking disease progression

Therapy development

Drug mechanism of action

Mutation/polymorphism

analysis

Detect mutations/polymorphisms

Drug development

Tracking disease progression

Disease risk assessment

Genotyping

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Herbal drug design

Herbal drugs – drug discovery from plants

Involves a multidisciplinary approach

Combining Botanical Ethnobotanical Phytochemical Biological techniques

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Historical perspective

morphine opium

quinine cinchona

cocaine

digitoxin foxflove

reserpine rauwolfia Hypotensive,tranquilizer

vincaleukoblastine Vinca rosea anticancer

vincristine Vinca rosea anticancer

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What should be the approach?

Collection of plants based on ethnopharmacological information or random screening

Standardise the extraction procedures Subject extract to pharmacologically relevant assays Isolation and characterisation of the active

compounds through bioassay directed fractionation Peridic reexamination of plant collections with new

screening systems

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Fractionation of tumor inhibitory extract

powdered leaves ( 1.5kg ) (Vernonia hymenolepis)

Conc.chloroform extract (87.0 gm )

10% aq.methanol interfacial solid petroleum ether extract (51.0gm ) (10.6gm ) extract (23.8gm)

silica gel chromatography

solvent 15% acetone in chloroform

Vernomenin (6.5gm),

Vernolepin ( 5.5gm)

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Recent discoveries

Drug properties plant

Paclitaxel

Camptothecin

Vinflunine

Anticancer agents Taxus brevifolia Nutt.

Camptotheca acuminata Decne.

Catharanthus roseus G.Don

Arteether Antimalarial drug Artemesia annua L.

Galanthamine Alzheimer”s disease

Galanthus Woronowii

Losinsk.

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Tiotropium Chronic obstructive pulmonary disease inhaled bronchodialator

Atropa belladona L.

Morphine 6-gluconoride

Pain medication Papaver somniferum L.

Calanolide A Anti HIV drugsantiretroviral and anti mycobacterial

agent,non-nucleoside reverse transcriptase inhibitor of type 1 HIV

Effective against AZT resistant strains of HIV

Calophyllum lanigerum var. austrocoriaceum

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NCE s from India

Flavopiridol tyrosine kinase activity and potent growth inhibitory activity against breast and lung carcinoma cell lines.

Dysoxylum binectariferum Hook.

Forskolin Potent adenylate cyclase activator

Semisynthetic derivative is approved for treatment of glaucoma

Coleus forskohlii Briq.

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Guggulsterone, [4,17,(20)-pregnadiene-3,16-dione]

Lowers serum LDL and triglyceride levels

highly efficacious antagonist of FXR

(farnesoid X receptor)

Commiphora mukul (Stocks)Engl.

Page 35: Introduction To Drug Discovery

Herbal product development

Herbal products are usually whole herbs, their formulations or extracts consisting of several bioactive compounds.

a paradigm shift from single-target drugs to multi-target drugs .

Multi-target approaches are directed toward activation of defence, protective repair mechanisms of the body rather than destruction of the damage-causing agent.

The concept of multi-targeted therapy exists in traditional medical treatments that employ multi-component extracts of natural products.

Page 36: Introduction To Drug Discovery

Standardisation of herbal products is difficult difficult to precisely predict the molecular targets, mechanism of

action and side effects for scientifically validated and standardized herbal product

there is a need for better understanding of the molecular mechanisms underlying their biological activity.

DNA microarrays provide a suitable high-throughput platform for research and development of drugs from natural productsthrough gene expression studies

allow rapid and detailed analysis of thousands of transcripts, providing a revolutionary approach to the investigation of gene expression.

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DNA Microarray - applications

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Microarray-based gene expression analysis of multi-component mixtures.

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In pharmacogenomics identification of genes involved in conferring drug

sensitivity or resistance. for prediction of potential side-effects of the herbal

drug during preclinical activity and safety studies (toxicogenomics)

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In pharmacognosy for correct botanical identification and authentication of crude plant materials as part of standardization and quality control

microarrays applied for the DNA sequence-based identification of medicinal plants using species specific probes

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Conclusion

Rich biodiversity Huge prospects for plant based drug

discovery and validation

Page 42: Introduction To Drug Discovery

THANK YOU