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an introduction to drug discovery
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HERBAL AND DRUG DESIGN TECHNOLOGY
Selma Siyavudeen
(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”.
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.
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
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
.
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).
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)
Insilico approach/computer assisted drug design (CADD)
Based on ligand receptor binding
Ligand based or receptor based designs
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
engage in a greater number of favorable interactions within the large carbonic anhydrase active site than can the smaller arylsulfonamides.
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.
STEP IILEAD OPTIMISATION
synthesize and test an exploratory series if analogues of the lead.
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
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
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
QSAR
parameters to account for hydrophobicity, topology, electronic properties, steric effects,
determined Empirically statistical analysis, computational methods.
chemical measurements and biological assays.
Step iiiLead Development
Preclinical testing
Clinical trials
Pharmacovigilance
Toxicology Pharmacokinetics/ADME Preformulation Formulation
Phase I,ii,iii,iv
Animal pharmacokinetic studies
ADME Studies using radioactive versions of NCE
Absorption Distribution Metabolism Excretion
Safety pharmacology Genotoxicity – gene mutations Acute toxicity testing Repeat toxicity testing Reproductive toxicology carcinogenicity
Toxicity testing
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
Clinical trials
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)
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
Advances in recombinant DNA technology - biopharmaceuticals
Blood products Clotting factors Anticoagulants Thrombolytic agents Recombinant vaccines
Haemopoetic growth factors
Interferons Interleukins Monoclonal antibody
based products
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
Herbal drug design
Herbal drugs – drug discovery from plants
Involves a multidisciplinary approach
Combining Botanical Ethnobotanical Phytochemical Biological techniques
Historical perspective
morphine opium
quinine cinchona
cocaine
digitoxin foxflove
reserpine rauwolfia Hypotensive,tranquilizer
vincaleukoblastine Vinca rosea anticancer
vincristine Vinca rosea anticancer
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
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)
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.
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
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.
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.
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.
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.
DNA Microarray - applications
Microarray-based gene expression analysis of multi-component mixtures.
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)
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
Conclusion
Rich biodiversity Huge prospects for plant based drug
discovery and validation
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