24-12-2012, 02:57 PM
DESIGN, SYNTHESIS, IN SILICO AND IN VIVO ANALYSIS OF INHIBITORS OF TROPICAL DISEASES
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Background
The term Tropical diseases encompasses all diseases that occur principally in tropics. This term
covers all communicable and non communicable diseases, genetic disorders and diseases caused by
nutritional deficiencies or environmental conditions (such as heat, humidity and altitude) that are
encountered in areas that lie between and alongside, the tropic of cancer and tropic of Capricorn belts.
In tropical countries, apart from non communicable diseases a severe burden of diseases is caused by
an array of different micro organism, parasites land and sea animals and arthropods. Given their poverty
weak public health systems; lack of education, and third world country location, tropical diseases
individually are often neglected by the international health community. The diseases can migrate to the more
developed countries and usually do effect travellers. The diseases are less prevalent in temperate climates,
due in part to the occurrence of a cold season which controls the insect population by forcing hibernation{1}.
Insects such as mosquitoes and flies are by far the most common disease carrier, or vector. These insects may
carry a parasite, bacterium or virus that is infectious to humans and animals. Most often disease is
transmitted by an insect "bite", which causes transmission of the infectious agent through subcutaneous
blood exchange. Vaccines are not available for most of the diseases, and many do not have cures.
Human exploration of tropical rainforests, deforestation, rising immigration and increased
international air travel and other tourism to tropical regions has led to an increased incidence of such
diseases.
Relation of climate to tropical diseases
The so-called "exotic" diseases in the tropics have long been noted both by travellers, explorers, etc.,
as well as by physicians. One obvious reason is that the hot climate present during all the year and the larger
volume of rains directly affect the formation of breeding grounds, the larger number and variety of natural
reservoirs and animal diseases that can be transmitted to humans, the largest number of possible insect
vectors of diseases. It is possible also that higher temperatures may favour the replication of pathogenic
agents both inside and outside biological organisms. Socio-economic factors may also in operation, since
most of the poorest nations of the world are in the tropics. Tropical countries like Brazil, which have
improved their socio-economic situation and invested in hygiene,public health and the combat of
transmissible diseases have achieved dramatic results in relation to the elimination or decrease of many
endemic tropical diseases in their territory. Climate change, global warming caused by the green house
effect, and the resulting increase in global temperatures are possibly causing tropical diseases and vectors to
spread to higher altitudes in mountainous regions, and to higher latitudes that were previously spared, such
as the Southern United States, the Mediterranean area etc.
Special Programme for Research and Training in Tropical Diseases (TDR)
In 1975 the Special Programme for Research and Training in Tropical Diseases (TDR) was
established to focus on neglected infectious diseases which disproportionately affect poor and marginalized
populations in developing regions of Africa, Asia, Central America and South America. It was established at
the World Health Organization, which is the executing agency, and is co-sponsored by the United Nations
Children's Fund, United Nations Development Programme, the World Bank and the World Health
Organization.
TDR's vision is to foster an effective global research effort on infectious diseases of poverty in
which disease endemic countries play a pivotal role. It has a dual mission of developing new tools and
strategies against these diseases, and to develop the research and leadership capacity in the countries where
the diseases occur. The TDR secretariat is based in Geneva, Switzerland, but the work is conducted
throughout the world through many partners and funded grants.
Open Source Drug Discovery(OSDD)
OSDD is a CSIR led team India Consortium with global partnership with a vision to provide
affordable healthcare to the developing world by providing a global platform where the best minds can
collaborate & collectively endeavour to solve the complex problems associated with discovering novel
therapies for neglected tropical diseases like Malaria, Tuberculosis, Leshmaniasis etc. OSDD is a
translational platform for drug discovery, bringing together informaticians, wet lab scientists, contract
research organizations, clinicians, hospitals and others who are willing to adhere to the affordable healthcare
philosophy. It is a concept to collaboratively aggregate the biological, genetic and chemical information
available to scientists in order to use it to hasten the discovery of drugs. This will provide a unique
opportunity for scientists, doctors, technocrats, students and others with diverse expertise to work for a
common cause. The success of Open Source models in Information Technology (For e.g., Web Technology,
The Linux Operating System) and Biotechnology (For e.g., Human Genome Sequencing) sectors highlights
the urgent need to initiate a similar model in healthcare, i.e., an Open Source model for Drug Discovery.
METHODOLOGY
Data mining and computational methods
For a medicinal product to reach patients,commonly, more than 8 years of time and millions of dollars in
investment are required to finish the long tedious drug development process. Furthermore only a handful can
finish the clinical trial and pass the strict inspection of drug regulatory agency,despite that thousands of new
therapeutic candidates are being discovered in laboratories every year. However, the recent advances in
technologies namely automated platform, computational chemistry and computer aided drug design
(CADD), are now offering a fast track to some limiting factors of therapeutic discovery as well. Computer
aided drug design(CADD) that offers an in silico alternative to medicinal chemistry techniques for studying
the structure and predicting the biological activity of drug candidates, has the advantages of both speed and
low cost and is becoming an in dispensable programme of major pharmaceutical companies.
Computer Aided Drug Design (CADD)
For those engaged in drug design, such as medicinal and computational chemists, the research phase
can be broken down into two main tasks: identification of new compounds showing some activity against a
target biological receptor, and the progressive optimization of these leads to yield a compound with
improved potency and physicochemical properties in-vitro, and eventually, improved efficacy,
pharmacokinetic, and toxicological profiles in-vivo. Identification of leads is driven either by random
screening or a directed design approach, and traditionally both strategies have been of equal importance,
depending on the problem in hand. The directed approach needs a rational starting point for medicinal
chemists and molecular modelling scientist to exploit. Examples include the design of analogues of a drug
known to be active against a target receptor and mimics of the natural substrate of an enzyme. Increasingly,
the three-dimensional structure of many biological targets is being revealed by X-ray crystallography and
nuclear magnetic resonance(NMR) spectroscopy.
Concept of Virtual Screening
Virtual screening uses computer based methods discover new ligand on the bases of biological
structure{8}. The basic goal of the virtual screening is the reduction of the enormous virtual chemical space
of small organic molecules, to synthesize and/or screen against a specific target protein, to a manageable
number of the compound that inhibit a highest chance to lead to a drug candidate {9}. In theory, the
applicability of virtual screening is limited only by what properties of a compound can be calculated
computationally and the perceived relevance of those properties to the problem in hand. On a practical level,
further considerations include the time-scale for calculation of the properties, which may be considerable for
a database of , say, one million compounds. The software and hardware required yielding a timely answer.
Many drug candidates fail in the clinical trials because of the reasons unrelated to the potency against
intended drug target. Pharmacokinetic & toxicity issues are blamed for more than half on the failure in the
clinical trials. Therefore first part of the visual screening evaluates the drug likeness of the same molecules
most independent of their intended drug target.
The term virtual screening has been used to describe a process of computationally analysing large
compound collections in order to prioritize compounds for synthesizes or assay. A broad range of
computational techniques can be applied to the problem. We can explicit receptor-ligand molecular
docking as a means of yielding the most detailed model of the way in which a given ligand will bind to a
receptor, and hence the most informative basis on which to assess which ligands are useful candidates for
synthesis or assay. Although the underlying methods of virtual screening have been in use in various guises
for several years, it is worth nothing the recent impact on molecular modelling made by the increased
availability of high - performance computing platforms. Affordable multiprocessor workstation and
PC(Personal Computer) clusters have enabled the modeller to employ computationally demanding
algorithms on a routine basis.