Insights into the inhibitory mechanism of a resveratrol and clioquinol hybrid against Aβ₄₂ aggregation and protofibril destabilization: A molecular dynamics simulation study

Abstract

Amyloid-β (Aβ) peptide instinctively aggregate and form plaques in the brain of Alzheimer’s disease (AD) patients. At present, there is no cure or treatment for AD, and significant effort has, therefore, been made to discover potent drugs against AD. Previous studies reported that a resveratrol and clioquinol hybrid compound [(E)-5-(4-hydroxystyryl)quinolone-8-ol], C1, strongly inhibit Aβ₄₂ aggregation and disassemble preformed fibrils. However, the atomic level details of the inhibitory mechanism of C1 against Aβ₄₂ aggregation and protrofibril disassembly remains elusive. In this regard, molecular docking and molecular dynamics (MD) simulation of Aβ₄₂ monomer, Aβ₄₂ monomer–C1 complex, Aβ₄₂ protofibril, and Aβ₄₂ protofibril–C1 complex were performed in the present study. MD simulations highlighted that C1 bind in the central hydrophobic core (CHC) region, i.e., KLVFF (16–20) of Aβ₄₂ monomer, which plays a critical role in Aβ₄₂ aggregation. C1 promote the formation of native helical conformation in the Aβ₄₂ monomer and decrease the probability of D23–K28 salt bridge interaction that is critical in the formation of aggregation-prone β-sheet conformation. Further, C1 destabilize Aβ₄₂ protofibril structure by increasing the interchain distance between chains A–B, disrupting the salt–bridge interaction between D23–K28, and decreasing the number of backbone hydrogen bonds between chains A–B of the Aβ₄₂ protofibril structure. The insights into the underlying inhibitory mechanism of small molecules that display potential in vitro anti–aggregation activity against Aβ₄₂ will be beneficial for the rational design of more potent drug molecules against AD.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• Alzheimer’s disease
• Aβ aggregation
• resveratrol and clioquinol hybrid
• molecular docking
• molecular dynamics simulation

Acknowledgements

Bhupesh Goyal (Sanction No: SB/FT/CS-013/2014) and Deepti Goyal (Sanction No: YSS/2015/000320) gratefully acknowledges Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India for the award of SERB Start-Up Research Grant (Young Scientists). Rajneet Kaur Saini is thankful to SERB-DST, India for the award of the fellowship. The authors acknowledge C-DAC, Pune for providing the C-DAC's supercomputing resources (PARAM Yuva-II) for the computational facilities. The authors acknowledge School of Chemistry & Biochemistry, Thapar Institute of Engineering & Technology (Deemed to be University), Patiala, Punjab and Department of Chemistry, Sri Guru Granth Sahib World University, Fatehgarh Sahib, Punjab, India for providing the research facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.