Bridging the gap between molecular descriptors and mechanism: cases studies by molecular dynamics simulations.
In recent years, both classification models and quantitative structure-activity relationships (QSARs) have been developed to discriminate the acute toxicity of polar narcotics and uncouplers. One of fundamental issues is how to select and interpret the molecular descriptors used in both methods. In this work, we first employed support vector machine on a dataset containing 155 polar narcotics and 19 uncouplers to filter the predictive hydrophobic and hydrogen bonding descriptors. Molecular dynamics simulations were then conducted to investigate the behavior of salicylate and pentachlorophenol molecules in the context of a palmitoyl-oleoyl-phosphatidylcholine lipid bilayer. The results demonstrated that their equilibrium properties in the lipid bilayer were closely associated with hydrophobic and hydrogen bonding descriptors. The preferable occupations of these molecules in the lipid bilayer were discussed in terms of their modes of toxic action. The observations from molecular dynamics simulations facilitated to elucidate the mechanism of polar narcotics and uncouplers.
Xu
Liang
L
Department of Engineering Mechanics, State Key Laboratory of Structural Analyses for Industrial Equipment, Dalian University of Technology, Dalian 116023, China.
Wang
Xicheng
X
Zhao
Weijie
W
D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D003198:Computer Simulation; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers; D008958:Models, Molecular; D015394:Molecular Structure; D009294:Narcotics / Q000737:chemistry* / Q000145:classification / Q000633:toxicity; D010416:Pentachlorophenol / Q000737:chemistry; D010636:Phenols / Q000737:chemistry* / Q000145:classification / Q000633:toxicity; D010713:Phosphatidylcholines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D020156:Salicylic Acid / Q000737:chemistry; D014475:Uncoupling Agents / Q000737:chemistry* / Q000145:classification / Q000633:toxicity
D008051:Lipid Bilayers; D009294:Narcotics; D010636:Phenols; D010713:Phosphatidylcholines; D014475:Uncoupling Agents; C034973:1-oleoyl-2-palmitoylphosphatidylcholine; D010416:Pentachlorophenol; D020156:Salicylic Acid