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In silico modeling of the molecular structure and binding of leukotriene A4 into leukotriene A4 hydrolase. | LitMetric

In silico modeling of the molecular structure and binding of leukotriene A4 into leukotriene A4 hydrolase.

Chem Biol Drug Des

Area de Química Física, Departamento de Química, Universidad Nacional de San Luis, Chacabuco 917, San Luis 5700, Argentina.

Published: December 2012

AI Article Synopsis

  • A study was conducted using molecular docking and in silico analysis to better understand the substrate leukotriene A4 (LTA4) and its product leukotriene B4 (LTB4) related to the enzyme leukotriene A4 hydrolase (LTA4H).
  • The molecular structures of LTA4 and LTB4 were examined using density functional theory (DFT), focusing on their configurations in different phases and breaking LTB4 into three parts for a detailed conformational analysis.
  • The findings led to a proposed binding model for LTA4 with LTA4H, showing how various forms of the molecules interact in the enzyme's active site, confirming compatibility with crystallographic data from LTA4H inhibitors.

Article Abstract

A combined molecular docking and molecular structure in silico analysis on the substrate and product of leukotriene A4 hydrolase (LTA4H) was performed. The molecular structures of the substrate leukotriene A4 (LTA4) and product leukotirene B4 (LTB4) were studied through density functional theory (DFT) calculations at the B3LYP/6-31 + G(d) level of theory in both gas and condensed phases. The whole LTB4 molecule was divided into three fragments (hydrophobic tail, triene motif, and a polar acidic group) that were subjected to a full conformational study employing the most stable conformations of them to build conformers of the complete molecule and geometry optimize further. LTA4 conformers' structures were modeled from the LTB4 minimum energy conformers. Both protonated and deprotonated species of LTA4 and LTB4 were analyzed according to pKa values found in the literature. Finally, a binding model of LTA4 with LTA4 hydrolase is proposed according to docking results that show intermolecular interactions that position the protonated and deprotonated ligand in the active site, in excellent agreement with the model suggested from LTA4H-inhibitors crystallographic data.

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Source
http://dx.doi.org/10.1111/cbdd.12037DOI Listing

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