title: Molecular interactions of 4-acetoxy-plakinamine B with peripheral anionic and other catalytic subsites of the aromatic gorge of acetylcholinesterase: computational and structural insights.
abstract: BACKGROUND
  A steroidal alkaloid, 4-acetoxy-plakinamine B (4APB), is a recently discovered marine natural product with inhibitory effect against acetylcholinesterase (AChE), but its mechanism of interaction with the enzyme remains to be elucidated.
  
  
  OBJECTIVE
  The main objective was to study molecular binding mode of the compound, its interactions with catalytic subsites and molecular mechanism behind its significant inhibitory effect.
  
  
  METHODS
  All possible interactions of ligands in the binding sites were analyzed using FRED 2.1 and the OMEGA pre-generated multi-conformer library.
  
  
  RESULTS
  Dipole-dipole interactions were observed between the secondary amino group of 4APB and Ser200 at a distance of 3.91 Å and also with Gly117 and Gly118. A further dipole-dipole interaction was between Arg289 and the heterocyclic nitrogen. Hydrogen bonding interactions were observed between Tyr130 and secondary amino and C-4 acetyl groups as well as between heterocyclic nitrogen and Phe288 at a distance of 3.04 Å. Hydrophobic interactions were evident between rings C/D of 4APB and with Phe288, Phe330 and Phe331. The computational studies revealed 4APB's critical molecular interaction with amino acids of peripheral active (PAS) and anionic (AS) subsites.
  
  
  CONCLUSIONS
  Our data provided molecular evidence for the mixed competitive inhibitory effect of 4APB. For lead optimization, structural insights revealed the N-methyl group of 4APB could be replaced by NH2 moiety to generate a more favorable hydrogen bonding with Glu199. A polar group insertion such as NH2 or OH at certain sites of the 4APB skeleton is also recommended.
  
  
  CONCLUSIONS
  These computational insights explained the mixed-competitive enzyme kinetic behavior of 4APB. This study outlines a strategy for designing novel derivatives of 4APB with potentially better AChE inhibitory activities through interaction at the PAS and AS sites.
authors.affiliation: Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. inam_marwat333@yahoo.com
authors.forename: Inamullah
authors.initials: I
authors.lastname: Khan
authors.forename: Abdus
authors.initials: A
authors.lastname: Samad
authors.forename: Amir Zada
authors.initials: AZ
authors.lastname: Khan
authors.forename: Solomon
authors.initials: S
authors.lastname: Habtemariam
authors.forename: Amir
authors.initials: A
authors.lastname: Badshah
authors.forename: Syed Muhammad
authors.initials: SM
authors.lastname: Abdullah
authors.forename: Naseem
authors.initials: N
authors.lastname: Ullah
authors.forename: Abuzar
authors.initials: A
authors.lastname: Khan
authors.forename: Muhammad
authors.initials: M
authors.lastname: Zia-Ul-Haq
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D013256:Steroids / Q000494:pharmacology*
chemical_list: C585129:4-acetoxyplakinamine B; D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D013256:Steroids; D000110:Acetylcholinesterase