Tuberculosis rates of co-infection with HIV-AIDS have increased

Tuberculosis is one of the top 10 causes of death
globally and according to latest available estimates, 10.4
million
people developed TB in 2016 out of which 4.9 million people were infected with
multidrug-resistant TB strains (MDR-TB) 1. Multidrug-resistant TB (MDR-TB) remains a public
health crisis and a health security threat. Moreover, the complications
aggravated by high rates of co-infection with HIV-AIDS have increased the
fatalities of this leading killer disease across the globe. Efforts to
eradicate the TB epidemic have been stepped up with renewed vigour through drug
discovery research, especially by adopting strategies oriented towards finding novel
drugs against the tubercle bacilli. Alanine racemase (EC 5.1.1.1; Alr), an
essential bacterial enzyme 2 catalyses the inter-conversion
of L- and D-alanine and has been recognised as a drug target for a long time
due to the absence of human homologs. Alr requires pyridoxal 5′-phosphate (PLP)
(attached to the enzyme through an internal Schiff’s base linkage) as a
cofactor in catalysis. In the L to D direction, the enzyme catalyses the
formation of D-alanine, an essential component of one of the precursors,
D-alanyl-D-alanine in the peptidoglycan layer of bacterial cell walls. Till
date, many inhibitors have been discovered against Alr in different pathogens 3,
4. A high-throughput screening for small molecule inhibitors by Anthony et
al. (2011) 5 led to the discovery
of several AlrMtb inhibitor leads out of which, five non-substrate
leads are non-toxic to mammalian cells Fig
1. Till date, there have been no studies concerning the mechanism of
inhibition of the leads in question. Considering the numerous hurdles in
culturing M.tb and the urgency in developing novel drugs to contain the
superbug strains, we sought to address the problem through computational
studies. We chose to investigate the dynamics
of the
enzyme with normal mode analysis over molecular dynamics
simulations as the latter is known to be computationally expensive, especially
if a large number of diverse conformations are desired. Refinement of inhibitor
target sites on the enzyme demanded that all possible conformations of the
enzyme be investigated. Therefore, NMA was more suitable for exploring
biologically relevant enzyme motions in comparison with MD simulations. Another
consideration was the limitation of MD to small motions over shorter time
scales when compared with the large-scale collective motions generated by NMA.
By performing comparative analyses across homologs with the help of a range of
computational tools including normal mode elastic network models, docking simulations,
structure analysis, we attempt to decipher the regulatory mechanism of
D-alanine synthesis in alanine racemases.

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