Computational chemistry is a branch of
Theoretical chemistry that uses a digital computation to model systems of
chemical interest. The increasing power and availability of computers and the
simultaneous development of well-tested and reliable theoretical methods. The
one of the computational chemistry as an adjunct to experimental research as
increased rapidly. Calculation ranging from few seconds to many hours of
computer time can serve as a guide to include less favourable reaction or
unstable products. In addition, advantage has taken to select more fruitful
procedures through many possible ways, in addition to modelling which enables
the researcher to examine them on a scale of space or time yet immeasurable by
experimental techniques. Thus computational chemistry yield information, which
may not be experimentally available. Computational chemistry refers to the
application of tools of information technology for storage, visualization,
interpretation, retrieval and acquisition of chemical data. In this book, I had
carried out the Quantitative Structure Activity Relationship (QSAR) and docking
studies of the derivatives of an antituberculosic agent PA-824 and had
initiated an attempt to develop a successful model by Quantitative Structure-
Activity Relationship techniques. These techniques were
used to develop correlation between biological activity and physiochemical
properties of a set of molecules. The limiting factor in the development of QSARs is the availability of
high quality experimental data. In QSAR analysis, it is
imperative that the input data be both accurate and precise to develop a
meaningful model. Docking
is a method, which predicts the preferred orientation of the ligand to the
receptor when bound to each other form a stable complex. The scoring functions may useful in
predicting the binding affinity between the ligand to the receptor.
Computational tools in chemistry such as Chem Sketch, Marvin Sketch, PASS,
OSIRIS and Molinspiration, Autodock and LAZAR has been used during the course
of the book. It is presumed that the results presented will be yet another drop
in the ocean of knowledge in medicinal chemistry.

The treatment of MDR-TB
is characterized by relatively less effective, poorly tolerated, and expensive
drugs that may need to be administered for years. Equally inadequate is the
treatment available for latent TB infection. It has been estimated that 2
billion individuals are infected with M. tuberculosis, so there is an enormous
human reservoir of the infecting organism. The currently recommended treatment
for latent TB infection is isoniazid given for 6–9 months. Because of the long
duration of this therapy and the potential toxicities of isoniazid, there is a
major compliance problem associated with the treatment regimen. Although new
drugs are needed to shorten the duration of treatment of latent TB infection,
the safety profile for these drugs must be excellent, because most patients
with latent infection are destined never to experience activation of their TB.

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                    Therefore, the need for
newer, more effective drugs that can achieve multiple goals in improving TB
control is pressing. Treatment of active disease needs to be shortened and
simplified. TB drug regimens should not interfere with the administration of
antiretroviral agents. Markedly improved therapy is needed for the treatment of
MDR-TB and XDR-TB, and the treatment of latent TB infection needs to be
dramatically shortened.

               Here in this book a number of
derivatives of an anti-tubercular agent PA-824 are evaluated using
computational tools with a view to establish its structure activity
relationship.PA-824 is an exciting candidate for the treatment of tuberculosis
and it is bactericidal against replicating and non-growing Mycobacterium tuberculosis.
The scope of this book on the derivatives of PA-824 may help to finding more
active antitubercular agent than PA-824.

 

 

Basics of QSAR

 

 

Tuberculosis (TB)

 

                                    Tuberculosis
continues to be a major public health problem throughout the world,
particularly in the developing countries. Nearly one-third of the global
population (two billion people) is infected with Mycobacterium tuberculosis and
is at risk of developing the disease. More than eight million people develop
active tuberculosis every year and about two million die of the disease. It is
the leading cause of death due to a single infectious agent among adults.
Tuberculosis is an infectious disease caused by the bacillus- Mycobacterium
tuberculosis and occasionally by Mycobacterium bovis and Mycobacterium
africanum. Tuberculosis commonly affects the lungs, but it can affect any other
organ in the body. The bacteria that cause tuberculosis usually spread through
air. When patient with infectious pulmonary tuberculosis coughs, sneezes or laughs,
bacilli are expelled into the air in the form of tiny droplets. These droplets
dry up rapidly to form droplet nuclei and may remain suspended in the air for
several hours. Adequate through and through ventilation removes and dilutes
these droplet nuclei, and direct sunlight quickly kills the bacilli, but they
can survive in the dark for several days. When a healthy person inhales these
droplet nuclei containing the tubercle bacilli, he/she may become infected.
Risk of infection an individual’s risk of infection depends on the extent of
exposure to an infectious source and susceptibility of the individual to
infection. The risk of infection is therefore high in a person who has close,
prolonged exposure to a person with sputum smear positive pulmonary TB. The
risk of transmission of infection from sputum smear-negative pulmonary TB is
low and with extra pulmonary TB, still lower.     

                      Tuberculosis develops in
two stages. The first stage occurs when the tubercle bacilli form an infectious
source enter the body of an individual but remain dormant without causing
disease and is called tuberculous infection. The second stage is when the
infected individual actually develops the disease and is called tuberculosis or
tuberculous disease.