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Molecular interactions of 4-acetoxy-plakinamine B with peripheral anionic and catalytic subsites of the aromatic gorge of acetylcholinesterase: Computational and structural insights

Molecular interactions of 4-acetoxy-plakinamine B with peripheral anionic and catalytic subsites of the aromatic gorge of acetylcholinesterase: Computational and structural insights

Khan, Inamullah, Samad, Abdus, Khan, Amir Zada, Habtemariam, Solomon, Badshah, Amir, Abdullah, Syed Muhammad, Ullah, Naseem, Khan, Abuzar and Zia-Ul-Haq, Muhammad (2013) Molecular interactions of 4-acetoxy-plakinamine B with peripheral anionic and catalytic subsites of the aromatic gorge of acetylcholinesterase: Computational and structural insights. Pharmaceutical Biology, 51 (6). pp. 722-727. ISSN 1388-0209 (Print), 1744-5116 (Online) (doi:10.3109/13880209.2013.764329)

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Abstract

Context: 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.

Materials and 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.

Discussion: 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.

Conclusion: 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.

Item Type: Article
Additional Information: [1] Copyright: © 2013, Informa Healthcare.
Uncontrolled Keywords: Acetylcholine, Alzheimer’s disease, docking, enzyme inhibition, marine natural products
Subjects: R Medicine > RM Therapeutics. Pharmacology
Faculty / Department / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > Department of Pharmaceutical, Chemical & Environmental Sciences
Related URLs:
Last Modified: 18 Nov 2016 16:16
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
URI: http://gala.gre.ac.uk/id/eprint/13427

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