title: Multi-target screening mines hesperidin as a multi-potent inhibitor: Implication in Alzheimer's disease therapeutics.
abstract: Alzheimer's disease (AD) is the most frequent form of neurodegenerative disorder in elderly people. Involvement of several pathogenic events and their interconnections make this disease a complex disorder. Therefore, designing compounds that can inhibit multiple toxic pathways is the most attractive therapeutic strategy in complex disorders like AD. Here, we have designed a multi-tier screening protocol combining ensemble docking to mine BACE1 inhibitor, as well as 2-D QSAR models for anti-amyloidogenic and antioxidant activities. An in house developed phytochemical library of 200 phytochemicals has been screened through this multi-target procedure which mine hesperidin, a flavanone glycoside commonly found in citrus food items, as a multi-potent phytochemical in AD therapeutics. Steady-state and time-resolved fluorescence spectroscopy reveal that binding of hesperidin to the active site of BACE1 induces a conformational transition of the protein from open to closed form. Hesperidin docks close to the catalytic aspartate residues and orients itself in a way that blocks the cavity opening thereby precluding substrate binding. Hesperidin is a high affinity BACE1 inhibitor and only 500 nM of the compound shows complete inhibition of the enzyme activity. Furthermore, ANS and Thioflavin-T binding assay show that hesperidin completely inhibits the amyloid fibril formation which is further supported by atomic force microscopy. Hesperidin exhibits moderate ABTS(+) radical scavenging assay but strong hydroxyl radical scavenging ability, as evident from DNA nicking assay. Present study demonstrates the applicability of a novel multi-target screening procedure to mine multi-potent agents from natural origin for AD therapeutics.
authors.affiliation: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India. Electronic address: sandipanchakraborty.13@gmail.com.
authors.forename: Sandipan
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Biotechnology, Maulana Abul Kalam University of Technology, West Bengal, BF-142, Salt Lake, Sector-1, Kolkata 700064, India.
authors.forename: Jaya
authors.initials: J
authors.lastname: Bandyopadhyay
authors.affiliation: DBT-IPLS Center, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India.
authors.forename: Sourav
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Microbiology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700 019, India. Electronic address: soumalee@gmail.com.
authors.forename: Soumalee
authors.initials: S
authors.lastname: Basu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D052160:Benzothiazoles / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D057225:Data Mining; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006569:Hesperidin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D015203:Reproducibility of Results; D013451:Sulfonic Acids / Q000737:chemistry
chemical_list: D000975:Antioxidants; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D013451:Sulfonic Acids; C002502:2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid; D004247:DNA; D006569:Hesperidin; D053829:Amyloid Precursor Protein Secretases
keywords: Anti-amyloidogenic; Antioxidant; BACE1; Ensemble docking; Multi-target screening; Phytochemicals