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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

Extended Double Bond Conjugation in the Chalcone Framework Favours MAO-B Inhibition: A Structural Perspective on Molecular Dynamics

Author(s): Clement Agoni, Abdul Rashid Issahaku, Mohamed A. Abdelgawad*, Ahmed Khames, Mahmoud E.S. Soliman* and Bijo Mathew*

Volume 25, Issue 12, 2022

Published on: 11 April, 2022

Page: [2059 - 2069] Pages: 11

DOI: 10.2174/1386207325666220214110717

Price: $65

Abstract

Background: The monotropic membrane protein monoamine oxidase B (MAO-B) has been shown to be a crucial drug target for the treatment of neurodegenerative diseases. The design of recent inhibitor therapeutic agents of MAO-B involves conjugation and modification of a chalcone scaffold comprising two aryl or heteroaryl rings connected via a short spacer unit with rotatable bonds. Supported by experimental data, these modifications often result in high potent inhibitor compounds.

Methods: In this study, we employ molecular dynamics simulations to unravel the impact of extended double bond conjugation in two novel compounds, F1 and MO10, toward the inhibition of the MAO-B protein. It was revealed that extended double bond conjugation induced a unidirectional orientation and motion of F1 and MO10, suggesting a stable binding pocket anchorage favouring high-affinity pocket interactions.

Results: Conformational analyses also revealed that the incorporated double bond extension impeded the motion of individual binding pocket residues, which subsequently disrupted the functionality of MAO-B.

Discussion: Real-time structural dynamics also revealed that the extended double bond conjugation mediated peculiar interactions with MAO-B binding pocket residues characterized by π-alkyl, π-π stacking, and π-sulphur interactions which buried both compounds into the hydrophobic core of MAO-B and ultimately induced higher binding affinities of both F1 and MO10.

Conclusion: These insights present useful structural perspectives of the extended double bond conjugation associated with the experimentally reported enhanced inhibitory activity of F1 and MO10 against MAO-B.

Keywords: Monoamine oxidase B, chalcone, molecular dynamics, neurodegenerative diseases, real-time structural dynamics, conformational analyses.

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