drug discovery anthony crasto
DESCRIPTION
DRUG DISCOVERYBY DR ANTHONY MELVIN CRASTO, WORLD DRUG TRACKERTRANSCRIPT
DRUG DISCOVERY OVERVIEWBY
DR ANTHONY MELVIN CRASTOWorlddrugtracker
http://newdrugapprovals.wordpress.com/
http://newdrugapprovals.wordpress.com/ http://www.allfordrugs.com/ http://worlddrugtracker.blogspot.in/ http://drug-scaleup-and-manufacturing.webnode.com/ http://amcrasto.wordpress.com/
is the link to my blogs which tracks drugs worldwide
US, CANADA, JAPAN, EU, CHINA , INDIA ETC
LINK
Dedicated to my son Lionel Crasto,
He was only in first standard in school (Dec 2007) when I was Paralysed head to
toe.
His smiling face sees me through day in and day out.
Vast readership from academia and industry motivates me, and keeps me going.
Helping millions with free advertisement free websites and has million hits on google
Thanks for helping me to keep lionel smiling
Shore Your own will power and determination will
reach you to the shore even if you are drowned in the middle of a storm
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.
Drug development process
Target
Right moleculeCandidate
drug
Preclinical documentat
ion
Clinical documentati
on
Drug Development7 years
Drug Discovery5-7 years
Drug discoveryThe 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 $800–1000 million
ProductsDrugsTargets & Leads
Target selection
Target to Lead
Lead to
candidate
Candidate selection to FTIH
FTIH to PoC
PoC to Commit to Phase III
Phase III
File & Launch
Lifecycle mgt
The Drug Discovery and Development process is a progression fromTargets and Leads… to Drugs...to Products
9 - 16 y
12-24m 12-24m 30-33m 8-12m 12-44m 0-30m 18-66m 10-13m
Costs ~ $1 billion per successful product
Drug Discovery and Development
Compound production
Manufacturing 0.5-2 years
Preclinical Clinical
FDA/EMEA review
Drug Discovery Drug Development Registration
Launch
PhI PhII PhIII PhIV
CD(Candidate Drug) NDA(New Drug Application)
QA and regulatory
PhI PhII PhIII
Drug DiscoveryDrug Development
RegistrationPreclinical
• GLP (Good Laboratory Practice)• GCP (Good Clinical Practice)• GMP(Good Manufacturing Practice)
NDANew Drug Application
INDInvestigational New Drug
(first time in man)
Preclinical
Intellectual Property, IP (Patents)
PhI PhII PhIII
Drug DiscoveryDrug Development
RegistrationPreclinical
Patents:•Structure class•Compound specific•Synthesis•Indication•Formulation•....
Patent time:•20 years from the filing date•Drug development 10-14 years
How to find the right molecule?
Process of drug discovery
Drug Discovery Process
chemical diversity
(compound library)
test safety&efficacyin animals and
humans
gene screen and identify lead
Lead
optimisationprotein target
DrugsTargets & Leads
Target Validation & Selection Target to Lead(compounds)
Lead to candidate
Drugs
Candidate progress to FTIH and PoC in
patients
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
Genome Disease
Potential Drug Target
Select protein of interest Pathology
Link with disease or disease process
Selection of Biological Target
Genetics
Target SelectionApproaches to Finding
a Drug Target
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
Screening to Generate Hits
Types of screens◦ Functional assay◦ Binding assay
Cell response
Compound binds to cell surface receptor - this can be measured
in a “binding assay”
This can evoke a cellularresponse - which can bemeasured in a “functionalassay”
Approaches 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 derivativ
es
Marine invertebrates
Microbial
metabolites
Virtual screen ( in silico)
Ligand based◦ Knowledge of other molecules
that bind to the target◦ Build on known
pharmacophore
Structure based ◦ Knowledge of three dimensional
structure of the target (X-ray or NMR)
◦ Docking
Potency In vitro
◦ Functional cell-based assays (FLIPR) Intracellular calcium mobilization (GCRP)
In vivo Species differences!◦ Potency in vivo?
Agonist induced models ( NK1 and NK2)
◦ Effective in IBS? Disease related models
Bioavailable
Permeability Metabolism
Organic Chemistry involved in Synthesis & Purification Organic chemists synthesize new drug compounds as well as isolate
and characterize natural products, such as alkaloids. In each case, there is interest in the complex relationships between chemical structure and pharmacological action.
The pharmacological activity of a compound is an involved function of the structure, and very small changes may pro-foundly modify the pharmacological effect.
These structural modifications may involve replacing one group with another at a specific point in the molecule, shifting the same group from place to place in the parent molecule, saturating valence bonds or modifying the acidity or basicity.
Total synthesis is made possible by knowledge of chemical structures and, in many instances, is important economically in reducing the cost of the drug.1 Chromatographic techniques have been widely used for the purification of newly synthesized compounds.
Involvement of different branches of Biological Sciences in New Drug Development
The first step in product characterization is to establish the precise chemical identity of the product. It is important to determine whether the material is a compound, i.e. a single chemical entity, a mixture of closely related compounds, mixture of isomers, or merely a loose molecular complex of readily dissociable components. Such information is fundamental to a proper evaluation of the biological properties of the material. For compounds of synthetic origin, identity is usually clearly defined in the great majority of cases by the synthetic route employed. However, it is essential not only that identity be confirmed by alternative means but that the means employed should be capable of providing rapid verification whenever this may be required at any stage of the development program. Modern spectroscopic techniques, such as as1H and 13C NMR and infrared spectroscopy are sensitive tools for such purposes.
Instrumental Techniques for Product Characterization
Once a new pharmaceutical lead compound has been discovered, extensive and costly efforts usually are made to prepare a series of analogues in the hope that even better activity will be found. In an effort to improve the efficiency of analogue development, a variety of statistical methods have been introduced.
They range from the Hansch approach, in which analysis of variance is used to derive an equation expressing the quantitative relationships between functional group changes and biologic activity, to pattern recognition and factor analysis methods
Statistical approaches in Drug Discovery
Preclinical documentation
Non-clinical risk and benefit assessment for◦ estimation of an initital safe starting dose in human◦ to support the clinical program
Studies◦ Pharmacodynamics◦ Pharmacokinetics◦ Toxicology
Regulatory guidelines Quality requirements
Phase I Phase II Phase IIII Registration
Carcinogenicity studies Rat and mouse 2 years dosing Expensive Critical timeline
Phase I Phase II Phase IIII
Part 2:Selecting a Drug Candidate
Topics
Lead optimisation – addition of extra properties (ADME)
Safety testingMolecules into MedicinesTesting in Humans
Optimizing Lead Compounds is an Iterative Process
MedicinalChemistry
Biology
Lead compounds from Screening
Candidate selected for testing in man
Developability
DMPK
Hypothesise, design molecules and synthesise
Analyse/rationaliseresults
Test hypothesis
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
confirmatio
n
• 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
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
Animals to Man
Conduct initial non-clinical safety studies to assess developability and potential risks for first administration to humans
Conduct additional studies to build confidence that longer term clinical trials can be conducted safely, and the medicine can be approved for use
To complete safety evaluation and assist in dose selection for first clinical trials, Safety Assessment has to:
Genetic damage? Carcinogenicity?
Aspects of a Safety Assessment
One dose Lifetime use
Acute Responses Chronic Effects
Reproduction
Development
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
Chemical Development (CD), in collaboration with
Pharmaceutical Development (PD), is charged with
delivering a cost effective, efficacious medicine...
Drug Substance (DS)Drug Substance (DS) Drug Product (DP)Drug Product (DP)
Molecules to Medicines
Drug Substance synthesis: Scale - up
10-100g
10-100kgLab scale
Factory scale
Consult with Regulatory Authorities
FDA:US Food and
Drug Administration
EMEA:European Medicines
Evaluation Agency
MHLW:Japan Ministry
of Health Labour
& Welfare
Agencies providehelpful insight into
study design and doses
Reduce risk of conducting long,
expensive studies that don’t lead
to approval
May change Phase III clinicalplan based on
feedback
Regulatory Authorities
Food and Drug Administration
European Medicines Agency
Ministry of Health Labour and Welfare
Therapeutic Goods Administration
Health Canada
International Conference on Harmonisation
Over 120 ‘International’ markets
Site needs=
Way to success Build on knowledge – creative ideas Scilled medicinal chemists Dedicated project team Serendipity and luck - prepared mind
Chemistry
Pharmacology
Toxicology Metabolis
mPK
[email protected] ANTHONY CRASTOchemistry sites https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-net
DR ANTHONY MELVIN CRASTO [email protected]
MOBILE-+91 9323115463GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
web linkhttp://anthonycrasto.jimdo.com/
http://www.anthonymelvincrasto.yolasite.com/ http://www.slidestaxx.com/anthony-melvin-crasto-phd
https://sites.google.com/site/anthonycrastoorganicchemistry/sites---my-own-on-the-nethttp://anthonycrasto.wordpress.com/
http://organicchemistrysite.blogspot.com/ http://www.mendeley.com/profiles/anthony-melvin-crasto/
Congratulations! Your presentation titled "Anthony Crasto Glenmark scientist, helping millions with websites" has just crossed MILLION views.
Thanks