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Computational Analysis of Triclosan as an InhA inhibitor in
Anti-TB Drug Discovery
Patrice Leahy ’04, Dr. Carlos Simmerling
Department of Chemistry, SUNY at Stony Brook
Stony Brook, NY 11794
It has been estimated that one third of the world’s population are infected with
Mycobacterium tuberculosis, the organism that causes tuberculosis, with 10% of these
people developing active infections, and more than two million people dying annually as
a result. Tuberculosis is presently treated with isoniazid and rifampicin. These drugs act
on InhA enzyme, the enoyl reductase enzyme in the mycobacterial fatty acid biosynthesis
pathway that is important for the survival of mycobacteria.
The recent pressing concern has been the emergence of multi-drug-resistant
tuberculosis (MDRTB) presenting a demand for new lead compounds to counteract these
resistant strains. In this study, we are looking at triclosan, an antibacterial additive in
consumer products, as a lead compound in the inhibition of InhA enzyme. The model
system used in this study is a homologue of InhA in other bacteria, such as E.coli, which
is commonly referred to as FabI. Although studies have found that triclosan is an
inhibitor of InhA, triclosan is a much stronger an inhibitor in FabI than it is in InhA.
The specific aim of this study was to increase our understanding of how triclosan
interacts with InhA and use it to increase its binding affinity of this compound for InhA.
Molecular dynamic simulations were performed on a 15 angstrom fragment of
InhA:NAD+:triclosan ternary complex with its active-site loop grafted in. These
simulations were used to look at the interaction of some existing triclosan analogs with
the wild-type enzyme and to analyze the impact of mutagenesis on analog binding.
Stipend support for PL was provided by a NSF funded Summer REU Chemistry
Internship at The State University of New York at Stony Brook .
Determine modifications to triclosan and mutants in the loop that result in ordering of the
substartate-binding loop in InhA upon binding. The proposal is that InhA, the enoyl
reductase enzyme in the mycobacterial fatty acid biosynthesis pathway, is a sensitive
target for anti-mycobacterial drug development. The drug discovery efforts have been
centered on triclosan, an antibacterial additive in consumer products, with an extremely
good toxicity profile in humans. However, although triclosan has been proven to be a
submicromolar inhibitor of Inha, it is not as effective of an inhibitor as it is in the Ecoli
system. Therefore, this study has been focused on making modifications to triclosan and
mutants in the loop that result in ordering of the substartate-binding loop in InhA upon
binding. To develop novel chemotherapeutics to treat MDRTB by looking at InhA, the
enoyl reductase enzyme in the mycobacterial fatty acid biosynthesis pathway, as a target
for anti-mycobacterial drug developmentLooking at InhA, , theTriclosan is a high affinity
inhibitor of FabI in Ecoli and therefore is widely used as an active ingredient in soaps and
toothpastes as an anti-bacterial agent. The computational methods used in this study are
molecular dynamics simulations.
Molecular Dynamics Simulation of Quartz Interactions with
Uranyl Ions and Bulk Water
Matthew Benard, Jeffery A. Greathouse, and Roberto T. Pabalan*
Department of Chemistry, St. Lawrence University, Canton, New
York 13617, and *Center for Nuclear Waste Regulatory Analysis,
Southwest Research Institute, 6220 Culebra Road, San Antonio,
Texas 78238
The government is currently debating as to whether or not Yucca Mountain, in
Nevada, should be used as a nuclear waste storage facility. The recent earthquake,
whose epicenter was merely twelve and a half miles from the site, has placed further
emphasis on understanding the interactions of such waste with the surrounding
environment. The waste would be stored underground, 1000 feet above the water table.
Due to the inescapable concern associated with the storage of nuclear materials, it is
important to have a firm understanding of mineral-solution interactions relevant to the
natural environment around Yucca Mountain. Abundant clay and other mineral surfaces
that surround Yucca Mountain include montmorillonite and vermiculite clay as well as
quartz.
We are currently studying the uranyl ion, UO22+ – the natural form of U (VI) in
groundwater. Molecular dynamics simulations were performed using the parallel code
DL_POLY. A flexible quartz surface was used to calculate surface energies and to
observe surface relaxation. Primarily all calculations were performed on the (001) crystal
face, in which three unique sub-surfaces, consisting of varied silicon-oxygen
conformations, were examined. Simulations of aqueous uranyl chloride were performed
with both rigid and flexible SPC water molecules. The effect of polarizable oxygen atoms
was investigated for both rigid and flexible water using the dynamical shell model.
Structural Analysis of Triclosan