Identification of effective natural compounds for reducing α-Synuclein aggregation involved in Parkinson’s disease using Molecular docking on the ZINC database

Parkinson's disease is one of the most common neurodegenerative disorders in the elderly age. One of themechanisms involved in neurodegeneration is related to the aggregation of the presynaptic protein α-synuclein. Despite numerous studies and efforts, discovering compounds that can serve as promisinginhibitors and delay α-synuclein aggregation remains an important challenge. This study aims to identifypotential compounds that inhibit α-synuclein accumulation using structure-based virtual screening in ZINC'snatural compounds Database. Initially, the structure of human α-synuclein covering the full sequence of theprotein (PDB ID:۱XQ۸) was retrieved and prepared from the Protein Data Bank. The natural compoundlibrary from the ZINC database that contains more than ۳۴۰,۰۰۰ compounds was prepared. The potential α-synuclein binding pocket contained was identified by the literature review. It contained four key residues,including L۳۸, V۴۰, K۴۳, and K۴۵, used to create docking constrain. Molecular docking studies at threedifferent precision levels, including HTVS (High throughput virtual screening), SP (standard precision), andXP (extra precision), were performed by Schrodinger ۲۰۲۱-۲. Subsequently, the MM-GBSA methodestimated the binding free energy between top-ranked ligands and the protein. The analysis of the moleculardocking calculation showed that the compounds ZINC۳۱۱۶۹۸۱۷ ()۱S(-۱,۵-Anhydro-۱-)۲,۶-dihydroxy-۴-methylphenyl(-D-glucitol), ZINC۱۲۴۰۵۲۰۲()۱R,۲S,۳R,۴S,۵R,۶S(-۶-Methoxy-۱,۲,۳,۴,۵-cyclohexanepentol), Compound۸۲۵ (}۳-)Hexopyranosyloxy(-۲-[(۲۷)-۲-penten-۱-yl]cyclopentyl}aceticacid) with docking score -۷.۹۹۸, -۷.۷۱۱, -۷.۲۲۵ Kcal/mol and the binding free energy -۲۹.۶۹, -۲۶.۵۷, -۲۸.۵۶have the highest affinity for interaction to α-synuclein monomer. The identified candidates need to verify bymolecular dynamics simulation before any in-invitro study.

کلیدواژه ها:

Parkinson’s disease ، α-synuclein ، aggregation ، Molecular docking ، ZINC Natural Library