Due largely to growing drug resistance, malaria and tuberculosis are two diseases that affect millions of people per year. Consequently, development of novel drugs for these diseases is a necessity. Isoprenoids are a class of vital biomolecules derived from the 5-carbon precursors, isopentenyl pyrophosphate (IPP) and dimethylally pyrophosphate (DMAPP). Recently, it was found that the isoprenoid biosynthetic pathway in organisms such as M. tuberculosis and P. falciparum (non-mevalonate pathway) differs from that in humans. Thus inhibition of enzymes in the non-mevalonate pathway is desirable for the development of potent anti-malarial and tuberculostatic drugs. IspH is a protein containing a 4Fe-4S cluster responsible for catalyzing the production of IPP and DMAPP from (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) in the terminal step of the non-mevalonate pathway. In this study, spin polarized broken symmetry density functional calculations are employed to complement classical molecular dynamics simulations of IspH to elucidate its mechanism and develop new inhibitors.

Studies of IspH mechanism and inhibition: Insight from density functional theory and classical molecular dynamics simulations

243rd National Meeting (2012)

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