Transcript Presentationof the project

Scientific project
«Screening of the bioactive substances from
the Central Asian flora to reveal
antituberculosis, antineoplastic,
neurotropic, antiviral and antiparasitic
agents»
The Institute of the Chemistry of Plant
Substances named after academician
S.Yu.Yunusov, Academy of Sciences,
Republic of Uzbekistan
What’s the problem?
In accordance with WHO calculations, infectious, oncologic,
viral infections, neurological disorders are included in the ten of
actual diseases affected to the Earth population.
Plant substances shown high biological activity in treatment of
tuberculosis, cancer, malaria, helminthiases, Alhzaimer disease
etc. But the range of known therapeutic remedies is not so
wide, while the medicine needs new drugs due to development
of pathogenes’ resistance to known drugs, side effects of
known drugs, as well as mutations and appearance of new
properties in strains of pathogenes.
Uzbek flora includes more 4500 species of wild growing plants,
1150 of them are used in medicine. Officially more 100 plant
species are included in Uzbek Pharmacopeia. Antituberculosis,
antineoplastic, neurotropic, antiviral, ahtiparasitic properties of
substances contain in these plants are not investigated
systematically.
Aim and objectives
• Aim of the project: screening of the biologically active substances
(alkaloids, terpenoids, phenolic substances and their derivatives),
determination, pharmacological and molecular investigation of
perspective leading substances for drug development.
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Objectives:
identification and comprehensive investigation of perspective plant
substances with antituberculosis, antineoplastic, neurotropic,
antiparasitic, antiviral activity,
investigation of their pharmacology and safety, mechanisms of
action,
creation of theoretical base for virtual screening of the investigated
classes of compounds, modeling of their interaction to cellular
targets,
preparation of qualified staff.
Planning activities under the project:
• Signing agreements on scientific collaboration and confidentity
between ICPS and scientific centers of EU, USA and China intend to
take part in the project. Formation and filing to international scientific
funds of four sub-projects aimed to investigation of separate kinds of
biological activity under this project is foreseen;
• Preparing of the library of substances isolated from the Central Asian
flora (alkaloids, terpenoids, phenolic substances and their
derivatives);
• Screening and investigation of biological activity of these substances
to reveal the leading substances with antituberculosis, antineoplastic,
neurotropic, antiparasitic/antiprotozoal (malaria, leishmaniasis,
helminthiases etc.), antiviral (hepatitis B and C, influenza and
haemorrhagic fevers etc.) activity;
• Modeling of interaction of the targeted substances to their molecular
targets, creation of systems for virtual screening of the investigated
classes of substances and kinds of biological activity;
• Investigation of pharmacology and safety of studied substances;
• Improvement of qualification of young scientists.
Sub-projects assumed inside this project
I. Screening, pharmacological and molecular investigation of
neurotropic (antagonistic to neurotoxins and nootropic) activity of
diterpene alkaloids of Aconitum and Delphinium plants
II. Screening, pharmacological and molecular investigation of
antituberculosis and antiparasitic/antiprotozoal activity of plant
substances isolated from the Central Asian flora and their
derivatives
III. Screening, pharmacological and molecular investigation of
antiviral activity of plant substances isolated from the Central Asian
flora and their derivatives
IV. Screening, pharmacological and molecular investigation of
antineoplastic activity of plant substances isolated from the Central
Asian flora and their derivatives
We assumed to use modern approaches
to investigation of biologically active
substances: systematic and total
screening, computer modeling of
interaction of studied substances and
pharmacological targets, structure-activity
relationship (SAR), instrumental and
biophysical methods of investigations etc.
Scientific experience and
investigation ability of the
Institute of the Chemistry of
Plant Substances – applicant
institution
The Institute of the Chemistry of Plant Substances named
after academician S.Yu.Yunusov, Academy of Sciences,
Republic of Uzbekistan (ICPS) is the scientific-investigation
institution realizes complex investigations in medicinal and
agricultural preparations development, including botanical,
chemical, pharmacological, toxicological study, computer
modeling of structures and properties of natural substances,
and manufacture of drug substances and preparations for
agriculture
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How did drugs develop in ICPS
Complex - «conveyor» system of drugs creation.
Botanical
investigation
Chemical
investigations
Working out technologies
for drug substances and
drug forms manufacture
Clinical
trials
Biological activity
screening
Pharmacological and
toxicological
investigations
Introduction into
practice
Institute
Institute’s structure and staff:
• 11 chemical laboratories
Organic synthesis department
Pharmacology and toxicology department
Technology department with Pilot manufacturing
Marketing department
Agency for certification of fertilizers, pesticides and
plants protection means and Testing center
• “Chemistry of Natural Compounds” Journal Publishers
• Mini printing office
• Library
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- 350 employers
Scientists - 160
DSci – 23, PhD - 77
Total staff
ICPS scientific activity
1.
2.
3.
4.
5.
Chemistry of natural compounds – isolation, structural
investigation and chemical modification of natural
compounds
Pharmacology and toxicology of natural compounds screening for different kinds of biological activity,
investigation of action mechanisms of natural and modified
substances as a base for new physiologically active
substances targeted search, and preclinical investigations
of candidate substances
Agricultural chemistry - creation of plant protection means
– plant growth stimulators, herbicides, fungicides,
defoliantes etc.
Preparations for veterinary – creation of preparations for
animal breeding and poultry
Phytopreparations technology – working out new effective
technologies, manufacture of drug substances and plant
protection means on Pilot manufacturing
Institute of the Chemistry of Plant Substances
is one of the world leading centers in
phytochemistry.
• More than 1200 alkaloids, 350 glycosides, 500
coumarines, flavonoids, lactones,
proanthocyanidines, 50 lipids and
30 polysaccharides have been isolated by scientists
of the Institute
• Molecular structures of 625 new alkaloids, 350 new
glycosides, 300 coumarines, flavonoids, terpenoids,
complex ethers, lactones and proanthocyanidines
have been elucidated
ICPS: phytochemical investigations and biological activity
screening
Alkaloids
1270 substances,
650 new
antiarrhythmic,
anticholinesterase,
sedative-tranquilizer,
antinociceptive,
antiinflammatory,
hypotensive,
anticonvulsant,
antituberculosis,
expectorant,
psychotropic and other
kinds of biological activity
Terpenoids
1000 substances,
430 new
Estrogenic,
angioprotective,
hypolipidemic,
antiinflammatory,
cardiotonic,
immunostimulative,
tonic etc.
Phenolic substances
more 500 substances,
270 new
Bile excreting,
bactericidal,
spasmolytic,
cardiotonic,
hypolipidemic,
antihypoxive,
photosensibilizing,
antiinflammatory etc.
ICPS: pharmacological and toxicological investigations of
plant substances
Pharmacological properties and molecular mechanisms of
2000 newly isolated plant substances belong to different
classes were characterized
New substances with
high antiarrhythmic,
antiatherosclerotic,
cardiotonic, hypotensive,
antitumor, psyhotropic,
neuroprotective,
curariform,
hepatoprotective,
antiinflammatory,
antidiabetic and other
types of biological
activity were identified.
In cooperation with
chemists and technologists
the drugs based on
phytoecdisteroids:
ecdisten, ajustan, exumide
as tonic, adaptogenic,
stress-protective remedies;
allapinine and aclesine as
antiarrhythmics;
dezoxypeganine,
galantamine as
anticholinesterase
remedies; tefestrol and
ferulen as estrogenic
remedies and other drugs
were introduced in
practice.
The relationship
between chemical
structure and
some kinds of
biological activity
were founded.
Pharmacophores
and toxophores
responsible to
biological activity
and toxicity were
determined.
ICPS: instrumental methods and computational simulation
104 diterpene alkaloids isolated from Aconitum and Delphinium
were investigated by molecular computational simulation
and QSAR
The most
significant
parameters
(descriptors)
responsible for
toxicity of
curariform,
antiarrhythmic and
other alkaloids
from this range
were founded
Algorithm for
selection of
informative
descriptors
significant for
displaying of
biological effects,
and construction of
prognostic
“structure-activity”
model was
proposed
High predictive
probabilistic
mathematical models
coupling the values of
physical-chemical and
quantum-chemical
indicative descriptors
and data in antiarrhythmic activity and
toxicity were obtained
for series from 65
diterpene alkaloids
It was shown, that diterpene alkaloids conform to the Rules of Lipinski.
In accordance with Rule of Lipinski these substances were divided to highperspective and low-perspective groups of potential drugs.
Technological achievements
Development of new profitable technologies of natural substances
Alkaloids
On the base of the
dependence of
alkaloids distribution in heterophase systems
from Rf и pH1/2
new technologies
for obtaining of
more 35 individual
physiologically
active alkaloids
were worked out.
Terpenoids
The original methods
for purification of
isoprenoids sum by
sorption from extract
the ballast substances
on ion-exchange resins
and isolation by liquidliquid extraction.
Technologies more 15
preparations based on
isoprenoids and their
glycosides were
worked out in
accordance with this
method.
Phenolic substances
Technologies for
manufacture of 10
preparations on
the base of
phenolic
substances were
worked out after
investigation of
sorption and
desorption of
phenolic
substances on
ion-exchange and
polyamide resins.
Medicines introduced in practice
Preparation
Prescription
Allapinin®
Antiarrhythmic
Galantamine ®
Choline esterase inhibitor
Desoxypeganine ®
Choline esterase inhibitor
Ecdisten ®
Actoprotector and adaptogenic
Тefestrol ®
Estrogenic
Оlygvon
Antiatherosclerotic
Cytizine
Analeptic
Cucumazime ®
Enzymatic (for surgery,
ophthalmology, “diabetic foot”
treatment etc.)
and others
How scientific work under the project should be organized
Foreign collaborators:
ICPS:
Isolation of individual plant
substances, identification of
structure, chemical
transformations
HTS, total screening
Pharmacology in vitro
Pharmacology and toxicology on
animal models using
pharmacological analyzers
Study of the interaction of the target
molecules to cellular targets using
molecular biology and electrophysiology
methods
Study of the interaction of the
target molecules to cellular
targets using computational
methods
Molecular docking
Study of the targeted pharmacological
activity of leading substances on genetic
animal models
Expected results
• Antituberculosis, antineoplastic, neurotropic,
antiparasitic, antiviral leading substances for drug
development will be recommended after screening,
pharmacological and molecular investigation.
• Theoretical base for development of virtual screening
systems for such classes of substances and modeling of
their interaction to cellular targets will be founded.
• Obtained results will be claimed in patents and
publications in scientific journals, as well as they will be
used for further chemical transformation of leading
substances in order to increasing their biological activity
or optimization of their properties.
• Perspective young scientists can improve their
qualification in leading scientific centers.
• The necessary equipment will be purchased.
Scientific funds for possible supporting
of the project
• «Horizon 2020» – 8th Framework Program of
European Union
• CRDF – US Civilian and Research Development
Foundation
• NSF – US National Scientific Foundation
• US National Health Institute
• Other international scientific funds open for
Uzbekistan
Contact person:
Firuza M.Tursunkhodjaeva, PhD
• position: senior scientist in the Pharmacology
and Toxicology Department, Institute of the
Chemistry of Plant Substances, Uzbek Academy
of Sciences
• phone: +998(71)262-72-85
• e-mail: [email protected];
[email protected]
http://uzicps.uz/