Computer-aided molecular modeling and structural Bioinformatics Studies for Identification and Design of Anti-tubercular and Anti-leishmanial agents

Abstract

From the very beginning of evolution, the symbiotic interaction between human host with the microorganisms or microbial world is very fascinating. At the time of evolution humans have developed a defence mechanism to combat several diseases. In spite of host defence mechanism, the parasite had developed several resistance mechanisms for survival. Diseases like small pox was observed in Egyptian mummies of around 3000-year-old 1. Also, the poliomyelitis the highly infected viral disease was portrayed in the paintings of the Egyptian papyrus 2. Hippocrates the first person who believed that diseases are caused by living habit, it can be airborne, waterborne, it is not a punishment given by God. He separated medicine from religion and became the founder of medicine 3. The observations of Girolamo fracastoro an Italian physician led to the development of germ theory 4. Before the acceptance of germ theory, the miasma theory was followed 5. The germ theory states that diseases are caused by microorganism whereas miasma theory states that diseases are caused due to foul air produced by rotten products 6. Better understanding of these microbial world exploration was done when for the very first time in 1600s Antonie Van Leeuwenhoek developed microscope 7. Things started becoming easier as people learned to cultivate and identify the microorganisms. For controlling and preventing diseases from microorganisms, vaccines were developed. Several preventive measures were taken like personal hygiene, nutrition and its importance in boosting immunity and health education. Pasteurization played important role in eliminating microbes 8. Antibiotics were then used against infection causing pathogens. Besides all these controls and preventive measures, the emergence of disease-causing pathogens is not completely controlled. The worldwide load of infectious disease is very high which need to be addressed properly. In this context, our project is primarily focussed on two of the important infectious diseases: leishmaniasis and tuberculosis. 1.2. Leishmaniasis Leishmaniasis a neglected tropical disease is caused when bitten by phlebotomine sand-fly 9. The genus Leishmania is obligate intracellular parasite of which 21 out of 30 species can cause infection to humans. It occurs mainly in three forms: Visceral, cutaneous and mucocutaneous 10. The visceral leishmaniasis (VL) is most severe form and is fatal if left untreated. It is known as ―kala-azar‖ in India, L.donovani is the causal organism in Africa and Asia, L. chagasi in the New World and L. infantum in the Mediterranean basin 11. It is known as neglected tropical disease because generally it affects low income population mostly occurring in the developing countries. The life cycle of leishmaniasis starts from the bite of female phlebotomine sand-flies. The sand fly injects promastigotes during the infective phase. Further the promastigotes in the blood are phagocytosed by macrophages. The process of conversion of promastigotes to amastigotes occurs in the blood. Subsequently, amastigotes affect different tissues and the clinical manifestation of leishmaniasis starts. Now the sandflies become infected when it bites the infected person. The amastigotes in the midgut of sand-fly divides into promastigotes and migrates to proboscis 12. It is characterized by anaemia, hepatomegaly, splenomegaly and fever. Post-kala-azar dermal leishmaniasis is also associated with it causing nodular rash and has been reported by patients from India and Sudan after treatment of visceral leishmaniasis 13. The incubation period of visceral, cutaneous and mucocutaneous ranges from 3-8 months, 2 weeks to several months and 1-3 months respectively 14. Leishmaniasis affect in following countries Sudan, South Sudan, India, Bangladesh, Nepal, brazil 15. About 95 % of the population is affected by cutaneous leishmaniasis and is the most common type among three and occurs mainly in turkey, Turkmenistan, Israel and Uzbekistan. Mucocutaneous affects about 90% of the population occurs in state of Bolivia, Peru and brazil, and the most endemic is visceral also known as kala azar affects more than 90% of the populations mostly in the Indian subcontinent and east Africa 16. The treatment includes the use of pentavalent antimonials, it was evident that parasites shows increased resistance and the failure cases was about 50% in Bihar and northern regions. Amphotericin B was very effective but later found to be toxic, but when given in liposomal form it was very effective and less toxic but was very expensive. Miltefosine was the first drug which can be taken orally and found to be effective 17.