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Multitarget Diallyl Disulfides (DADS) against Aβ Aggregation: Screening through Molecular Docking with Aβ 42 & Zn II ‐Aβ 16 , ADME, DFT & Synthetic Strategy
Author(s) -
Singhal Sugandha,
Khanna Pankaj,
Misra Neeti,
Khanna Leena
Publication year - 2021
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.202004635
Subject(s) - chemistry , protein data bank (rcsb pdb) , docking (animal) , chelation , curcumin , stereochemistry , combinatorial chemistry , biochemistry , organic chemistry , medicine , nursing
The Aβ 42 amyloid aggregation and its stabilization by coordination metals like Zn II through chelation, are the major pathological causes behind the occurrence of Alzheimer's disease (AD). Natural compounds like curcumin and chrysamine G have depicted Aβ 42 aggregation inhibition, metal chelation and anti‐oxidant properties. Likewise garlic derived diallyl disulfide (DADS) has shown metal chelation, acetylcholinesterase (AChE) inhibition and antioxidant properties. In the present study a library of thirty four unnatural symmetrical DADS derivatives with aliphatic, aryl and new heteroaryl spacer groups, has been designed on the basis of electron releasing/withdrawing substituents and N/O heteroatom. The library was screened using various theoretical tools for their molecular properties and bioactivity with different receptors, to filter eleven potentially active derivatives. Further, Molecular docking study with Aβ 42 (PDB ID: 1IYT) and Zn II ‐Aβ 16 (PDB ID: 1ZE9) displayed significant binding of heteroaryl DADS derivatives with highest binding energies and zinc binding ability. DFT calculations helped to predict their binding ability with free Zn II ion through disulfide linkage. MEP studies specified their reactive sites of binding. Finally, a synthetic protocol using less toxic reagents has been designed for their synthesis and an in vitro antioxidant activity has been evaluated.