Older patients with existing cardiorespiratory illness undergoing major surgery have a reduced morbidity and mortality when dobutamine is used to maximize oxygen transport.
Dihydrofolate
reductase (DHFR), a key enzyme involved in folate
metabolism, is a widely explored target in the treatment of cancer,
immune diseases, bacteria, and protozoa infections. Although several
antifolates have proved successful in the treatment of infectious
diseases, they have been underexplored to combat tuberculosis, despite
the essentiality of M. tuberculosis DHFR (MtDHFR).
Herein, we describe an integrated fragment-based drug discovery approach
to target MtDHFR that has identified hits with scaffolds not yet explored
in any previous drug design campaign for this enzyme. The application
of a SAR by catalog strategy of an in house library for one of the
identified fragments has led to a series of molecules that bind to
MtDHFR with low micromolar affinities. Crystal structures of MtDHFR
in complex with compounds of this series demonstrated a novel binding
mode that considerably differs from other DHFR antifolates, thus opening
perspectives for the development of relevant MtDHFR inhibitors.
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