TY - JOUR
T1 - Structure-Based Optimization of Pyridoxal 5′-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis
AU - Liu, Feng
AU - Dawadi, Surendra
AU - Maize, Kimberly M.
AU - Dai, Ran
AU - Park, Sae Woong
AU - Schnappinger, Dirk
AU - Finzel, Barry C.
AU - Aldrich, Courtney C.
N1 - Funding Information:
This research also used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The authors also acknowledge the use of beamline 4.2.2 (Molecular Biology Consortium) at the Advanced Light Source and thank the beamline director, Jay Nix. This research used resources of the Advanced Light Source, which is a DOE Office of Science User Facility under contract no. DE-AC02-05CH11231.
PY - 2017/7/13
Y1 - 2017/7/13
N2 - The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium.
AB - The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium.
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U2 - 10.1021/acs.jmedchem.7b00189
DO - 10.1021/acs.jmedchem.7b00189
M3 - Article
C2 - 28594172
AN - SCOPUS:85023759354
VL - 60
SP - 5507
EP - 5520
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 13
ER -