5 research outputs found
Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat
Xanthine oxidase (XO) is a member of the molybdopterin-containing
enzyme family. It interconverts xanthine to uric acid as the last
step of purine catabolism in the human body. The high uric acid concentration
in the blood directly leads to human diseases like gout and hyperuricemia.
Therefore, drugs that inhibit the biosynthesis of uric acid by human
XO have been clinically used for many years to decrease the concentration
of uric acid in the blood. In this study, the inhibition mechanism
of XO and a new promising drug, topiroxostat (code: FYX-051), is investigated
by employing molecular dynamics (MD) and quantum mechanics/molecular
mechanics (QM/MM) calculations. This drug has been reported to act
as both a noncovalent and covalent inhibitor and undergoes a stepwise
inhibition by all its hydroxylated metabolites, which include 2-hydroxy-FYX-051,
dihydroxy-FYX-051, and trihydroxy-FYX-051. However, the detailed mechanism
of inhibition of each metabolite remains elusive and can be useful
for designing more effective drugs with similar inhibition functions.
Hence, herein we present the computational investigation of the structural
and dynamical effects of FYX-051 and the calculated reaction mechanism
for all of the oxidation steps catalyzed by the molybdopterin center
in the active site. Calculated results for the proposed reaction mechanisms
for each metabolite’s inhibition reaction in the enzyme’s
active site, binding affinities, and the noncovalent interactions
with the surrounding amino acid residues are consistent with previously
reported experimental findings. Analysis of the noncovalent interactions
via energy decomposition analysis (EDA) and noncovalent interaction
(NCI) techniques suggests that residues L648, K771, E802, R839, L873,
R880, R912, F914, F1009, L1014, and A1079 can be used as key interacting
residues for further hybrid-type inhibitor development
Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat
Xanthine oxidase (XO) is a member of the molybdopterin-containing
enzyme family. It interconverts xanthine to uric acid as the last
step of purine catabolism in the human body. The high uric acid concentration
in the blood directly leads to human diseases like gout and hyperuricemia.
Therefore, drugs that inhibit the biosynthesis of uric acid by human
XO have been clinically used for many years to decrease the concentration
of uric acid in the blood. In this study, the inhibition mechanism
of XO and a new promising drug, topiroxostat (code: FYX-051), is investigated
by employing molecular dynamics (MD) and quantum mechanics/molecular
mechanics (QM/MM) calculations. This drug has been reported to act
as both a noncovalent and covalent inhibitor and undergoes a stepwise
inhibition by all its hydroxylated metabolites, which include 2-hydroxy-FYX-051,
dihydroxy-FYX-051, and trihydroxy-FYX-051. However, the detailed mechanism
of inhibition of each metabolite remains elusive and can be useful
for designing more effective drugs with similar inhibition functions.
Hence, herein we present the computational investigation of the structural
and dynamical effects of FYX-051 and the calculated reaction mechanism
for all of the oxidation steps catalyzed by the molybdopterin center
in the active site. Calculated results for the proposed reaction mechanisms
for each metabolite’s inhibition reaction in the enzyme’s
active site, binding affinities, and the noncovalent interactions
with the surrounding amino acid residues are consistent with previously
reported experimental findings. Analysis of the noncovalent interactions
via energy decomposition analysis (EDA) and noncovalent interaction
(NCI) techniques suggests that residues L648, K771, E802, R839, L873,
R880, R912, F914, F1009, L1014, and A1079 can be used as key interacting
residues for further hybrid-type inhibitor development
Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat
Xanthine oxidase (XO) is a member of the molybdopterin-containing
enzyme family. It interconverts xanthine to uric acid as the last
step of purine catabolism in the human body. The high uric acid concentration
in the blood directly leads to human diseases like gout and hyperuricemia.
Therefore, drugs that inhibit the biosynthesis of uric acid by human
XO have been clinically used for many years to decrease the concentration
of uric acid in the blood. In this study, the inhibition mechanism
of XO and a new promising drug, topiroxostat (code: FYX-051), is investigated
by employing molecular dynamics (MD) and quantum mechanics/molecular
mechanics (QM/MM) calculations. This drug has been reported to act
as both a noncovalent and covalent inhibitor and undergoes a stepwise
inhibition by all its hydroxylated metabolites, which include 2-hydroxy-FYX-051,
dihydroxy-FYX-051, and trihydroxy-FYX-051. However, the detailed mechanism
of inhibition of each metabolite remains elusive and can be useful
for designing more effective drugs with similar inhibition functions.
Hence, herein we present the computational investigation of the structural
and dynamical effects of FYX-051 and the calculated reaction mechanism
for all of the oxidation steps catalyzed by the molybdopterin center
in the active site. Calculated results for the proposed reaction mechanisms
for each metabolite’s inhibition reaction in the enzyme’s
active site, binding affinities, and the noncovalent interactions
with the surrounding amino acid residues are consistent with previously
reported experimental findings. Analysis of the noncovalent interactions
via energy decomposition analysis (EDA) and noncovalent interaction
(NCI) techniques suggests that residues L648, K771, E802, R839, L873,
R880, R912, F914, F1009, L1014, and A1079 can be used as key interacting
residues for further hybrid-type inhibitor development
Unleashing the Potential of 1,3-Diketone Analogues as Selective LH2 Inhibitors
Lysyl hydroxylase 2 (LH2) catalyzes the formation of
highly stable
hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus
promoting lung cancer metastasis through its capacity to modulate
specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening
(HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1–18, and identified 12 and 13 that inhibit LH2 with IC50’s of approximately
300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum
mechanics/molecular mechanics (QM/MM) modeling indicates that the
selectivity of 12 and 13 may stem from noncovalent
interactions like hydrogen bonding between the morpholine/piperazine
rings with the LH2-specific Arg661. Treatment of 344SQ WT cells with 13 resulted in a dose-dependent reduction in their migration
potential, whereas the compound did not impede the migration of the
same cell line with an LH2 knockout (LH2KO)
Unleashing the Potential of 1,3-Diketone Analogues as Selective LH2 Inhibitors
Lysyl hydroxylase 2 (LH2) catalyzes the formation of
highly stable
hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus
promoting lung cancer metastasis through its capacity to modulate
specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening
(HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1–18, and identified 12 and 13 that inhibit LH2 with IC50’s of approximately
300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum
mechanics/molecular mechanics (QM/MM) modeling indicates that the
selectivity of 12 and 13 may stem from noncovalent
interactions like hydrogen bonding between the morpholine/piperazine
rings with the LH2-specific Arg661. Treatment of 344SQ WT cells with 13 resulted in a dose-dependent reduction in their migration
potential, whereas the compound did not impede the migration of the
same cell line with an LH2 knockout (LH2KO)