Discovery and Biophysical Evaluation of First Low Nanomolar Hits Targeting CYP125 of M. tuberculosis.
Tuberculosis, which is predominantly caused by Mycobacterium tuberculosis (Mtb), is still the most lethal bacterial infection with 1.5 million casualties in 2014. Moreover, the fact that the appearance of resistant mutants and long-term treatment are coupled with economic problems in developing countries hampers an efficient therapy. Interference with the essential cholesterol metabolism of Mtb could be a promising novel strategy to fight Mtb infections. CYP125, a P450 enzyme in Mtb, has been shown to play an important role in this metabolic pathway. For this reason, we used a combined screening approach involving surface plasmon resonance spectroscopy and a heme coordination assay to identify new CYP125 binders by employing a focused P450-inhibitor library. We identified the first hits with high affinity and favorable ligand efficiencies. Furthermore, frontrunner compounds also showed selectivity toward CYP121 specific to Mtb and required for its survival. To date, these are the first compounds targeting CYP125 with low nanomolar affinity.
Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E8.1, 66123, Saarbrücken, Germany.
Christian
C
Brengel
Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E8.1, 66123, Saarbrücken, Germany.
Andreas
A
Thomann
Department of Biochemistry, Saarland University, Campus B2.2, 66123, Saarbrücken, Germany.
Alexander
A
Schifrin
Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E8.1, 66123, Saarbrücken, Germany.
Jens
J
Eberhard
Helmholtz Institute for Pharmaceutical Research Saarland, Department of Drug Design and Optimization, Campus E8.1, 66123, Saarbrücken, Germany.|Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123, Saarbrücken, Germany.
Rolf W
RW
Hartmann
Mycobacterium tuberculosis; anti-infectives; biophysics; inhibitors; screening