Structure-activity relationships of diphenyl-ether as protoporphyrinogen oxidase inhibitors: insights from computational simulations.
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4), which has been identified as a significant target for a great family of herbicides with diverse chemical structures, is the last common enzyme responsible for the seventh step in the biosynthetic pathway to heme and chlorophyll. Among the existing PPO inhibitors, diphenyl-ether is the first commercial family of PPO inhibitors and used as agriculture herbicides for decades. Most importantly, diphenyl-ether inhibitors have been found recently to possess the potential in Photodynamic therapy (PDT) to treat cancer. Herein, molecular dynamics simulations, approximate free energy calculations and hydrogen bond energy calculations were integrated together to uncover the structure-activity relationships of this type of PPO inhibitors. The calculated binding free energies are correlated very well with the values derived from the experimental k (i) data. According to the established computational models and the results of approximate free energy calculation, the substitution effects at different position were rationalized from the view of binding free energy. Some outlier (e.g. LS) in traditional QSAR study can also be explained reasonably. In addition, the hydrogen bond energy calculation and interaction analysis results indicated that the carbonyl oxygen on position-9 and the NO(2) group at position-8 are both vital for the electrostatic interaction with Arg98, which made a great contribution to the binding free energy. These insights from computational simulations are not only helpful for understanding the molecular mechanism of PPO-inhibitor interactions, but also beneficial to the future rational design of novel promising PPO inhibitors.
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, Hubei, People's Republic of China.
Ge-Fei
GF
Hao
Ying
Y
Tan
Ning-Xi
NX
Yu
Guang-Fu
GF
Yang
D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D016941:Myxococcus xanthus / Q000201:enzymology*; D010647:Phenyl Ethers / Q000737:chemistry* / Q000494:pharmacology*; D050768:Protoporphyrinogen Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D010647:Phenyl Ethers; C031538:phenyl ether; D050768:Protoporphyrinogen Oxidase
Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8895-900
9238074
J Biol Chem. 1988 Mar 15;263(8):3835-9
3346226
Pest Manag Sci. 2004 Dec;60(12):1178-88
15578598
EMBO J. 2004 Apr 21;23(8):1720-8
15057273
Plant Physiol. 1985 Jun;78(2):215-20
16664219
Arch Dermatol Res. 1994;286(6):300-3
7979545
Biochim Biophys Acta. 2003 Aug 21;1650(1-2):10-21
12922165
Plant Physiol. 1991 Sep;97(1):197-203
16668371
Biochem J. 1991 Jul 1;277 ( Pt 1):17-21
1854333
Anal Biochem. 2005 Sep 1;344(1):115-21
16039600
Cancer Res. 1997 Oct 15;57(20):4551-6
9377568
Acc Chem Res. 2000 Dec;33(12):889-97
11123888
J Comput Chem. 2005 Dec;26(16):1668-88
16200636
J Comput Chem. 2004 Jul 15;25(9):1157-74
15116359
PLoS One. 2010 May 20;5(5):e10742
20505777
J Photochem Photobiol B. 2009 Jul 17;96(1):1-8
19406659
Biochem J. 1964 Jan;90(1):69-75
5832302
J Phys Chem B. 2010 Jul 29;114(29):9663-76
20604558
J Struct Biol. 2010 Apr;170(1):76-82
19944166
Arch Biochem Biophys. 1984 Feb 15;229(1):312-9
6703698
J Biol Chem. 1975 Feb 25;250(4):1269-74
234450
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10553-8
9724741
Acta Ophthalmol. 2009 Mar;87(2):118-32
18577193
J Biol Chem. 1976 Jun 25;251(12):3730-3
6461
J Biol Chem. 2006 Dec 15;281(50):38625-33
17046834
J Photochem Photobiol B. 1990 Jun;6(1-2):143-8
2121931
Biochem J. 1989 May 15;260(1):231-5
2775186
J Phys Chem B. 2010 Jan 28;114(3):1479-85
20043649
Photodiagnosis Photodyn Ther. 2009 Sep-Dec;6(3-4):159-66
19932447
Protein Sci. 1996 Jan;5(1):98-105
8771201
J Phys Chem B. 2009 Apr 9;113(14):4865-75
19284797
Biochem Biophys Res Commun. 1996 Sep 4;226(1):226-30
8806618