Computational comparison of imidazoline association with the 12 binding site in human monoamine oxidases

Livia Basile, Matteo Pappalardo, Salvatore Guccione*, Danilo Milardi, Rona R. Ramsay

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Imidazoline ligands in I2-type binding sites in the brain alter monoamine turnover and release. One example of an 12 binding site characterized by binding studies, kinetics, and crystal structure has been described in monoamine oxidase B (MAO B). MAO A also binds imidazolines but has a different active site structure. Docking and molecular dynamics were used to explore how 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) binds to MAO A and to explain why tranylcypromine increases tight binding to MAO B. The energy for 2-BFI binding to MAO A was comparable to that for tranylcypromine-modified MAO B, but the location of 2-BFI in the MAO A could be anywhere in the monopartite substrate cavity. Binding to the tranylc-ypromine-modified MAO B was with high affinity and in the entrance cavity as in the crystal structure, but the energies of interaction with the native MAO B were less favorable. Molecular dynamics revealed that the entrance cavity of MAO B after tranylcypromine modification is both smaller and less flexible. This change in the presence of tranylcypromine may be responsible for the greater affinity of tranylcypromine-modified MAO B for imidazoline ligands.

Original languageEnglish
Pages (from-to)1200-1207
Number of pages8
JournalJournal of Chemical Information and Modeling
Volume54
Issue number4
DOIs
Publication statusPublished - Apr 2014

Keywords

  • MOLECULAR-DYNAMICS
  • LIGAND-BINDING
  • HUMAN BRAIN
  • INHIBITION
  • POTENTIATION
  • TRANYLCYPROMINE
  • DERIVATIVES
  • RESOLUTION
  • RECEPTORS
  • LIVER

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