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Int. J. Mol. Sci. 2017, 18(5), 761; doi:10.3390/ijms18050761

3D-QSAR, Molecular Docking and Molecular Dynamics Simulation of Pseudomonas aeruginosa LpxC Inhibitors

1,†
,
1,†
,
1
,
1
,
1
,
1,* , 2
and
1,3,*
1
College of Pharmacy and Biological Engineering, Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610106, China
2
College of Mathematics and Informatics, South China Agricultural University, Guangzhou 510642, China
3
College of Chemistry, Leshan Normal University, Leshan 614004, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Lyle Isaacs
Received: 11 February 2017 / Revised: 17 March 2017 / Accepted: 26 March 2017 / Published: 6 May 2017
(This article belongs to the Section Molecular Recognition)
View Full-Text   |   Download PDF [6353 KB, uploaded 6 May 2017]   |  

Abstract

As an important target for the development of novel antibiotics, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) has been widely studied. Pyridone methylsulfone hydroxamate (PMH) compounds can effectively inhibit the catalytic activity of LpxC. In this work, the three-dimensional quantitative structure-activity relationships of PMH inhibitors were explored and models with good predictive ability were established using comparative molecular field analysis and comparative molecular similarity index analysis methods. The effect of PMH inhibitors’ electrostatic potential on the inhibitory ability of Pseudomonas aeruginosa LpxC (PaLpxC) is revealed at the molecular level via molecular electrostatic potential analyses. Then, two molecular dynamics simulations for the PaLpxC and PaLpxC-inhibitor systems were also performed respectively to investigate the key residues of PaLpxC hydrolase binding to water molecules. The results indicate that orderly alternative water molecules can form stable hydrogen bonds with M62, E77, T190, and H264 in the catalytic center, and tetracoordinate to zinc ion along with H78, H237, and D241. It was found that the conformational transition space of PaLpxC changes after association with PMH inhibitors through free energy landscape and cluster analyses. Finally, a possible inhibitory mechanism of PMH inhibitors was proposed, based on our molecular simulation. This paper will provide a theoretical basis for the molecular design of LpxC-targeting antibiotics. View Full-Text
Keywords: drug-resistance; LpxC; methylsulfone hydroxamate; 3D-QSAR; molecular dynamics simulation; free energy landscape; inhibitory mechanism drug-resistance; LpxC; methylsulfone hydroxamate; 3D-QSAR; molecular dynamics simulation; free energy landscape; inhibitory mechanism
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Zuo, K.; Liang, L.; Du, W.; Sun, X.; Liu, W.; Gou, X.; Wan, H.; Hu, J. 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation of Pseudomonas aeruginosa LpxC Inhibitors. Int. J. Mol. Sci. 2017, 18, 761.

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