β-Secretase-1: In Silico Drug Reposition for Alzheimer’s Disease

Galeana-Ascencio, Roberto A.; Mendieta, Liliana; Limón, Daniel; Gnecco, Dino; Terán, Joel L.; Orea, María L.; Carrasco-Carballo, Alan

doi:10.3390/ijms24098164

Cited by 3 publications

(3 citation statements)

References 43 publications

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“…Verubescestat [62]. Luteolin had a BCE of −5.539 kcal/mol and presented two hydrogen bond interactions (Gly 229 and Tyr 197).…”

Section: App Secretase Regulationmentioning

confidence: 99%

Ginkgo biloba: Antioxidant Activity and In Silico Central Nervous System Potential

Suárez-González,

Sandoval-Ramírez,

Flores-Hernández

et al. 2023

CIMB

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Ginkgo biloba (GB) extracts have been used in clinical studies as an alternative therapy for Alzheimer’s disease (AD), but the exact bioaction mechanism has not yet been elucidated. In this work, an in silico study on GB metabolites was carried out using SwissTargetPrediction to determine the proteins associated with AD. The resulting proteins, AChE, MAO-A, MAO-B, β-secretase and γ-secretase, were studied by molecular docking, resulting in the finding that kaempferol, quercetin, and luteolin have multitarget potential against AD. These compounds also exhibit antioxidant activity towards reactive oxygen species (ROS), so antioxidant tests were performed on the extracts using the DPPH and ABTS techniques. The ethanol and ethyl acetate GB extracts showed an important inhibition percentage, higher than 80%, at a dose of 0.01 mg/mL. The effect of GB extracts on AD resulted in multitarget action through two pathways: firstly, inhibiting enzymes responsible for degrading neurotransmitters and forming amyloid plaques; secondly, decreasing ROS in the central nervous system (CNS), reducing its deterioration, and promoting the formation of amyloid plaques. The results of this work demonstrate the great potential of GB as a medicinal plant.

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“…Verubescestat [62]. Luteolin had a BCE of −5.539 kcal/mol and presented two hydrogen bond interactions (Gly 229 and Tyr 197).…”

Section: App Secretase Regulationmentioning

confidence: 99%

Ginkgo biloba: Antioxidant Activity and In Silico Central Nervous System Potential

Suárez-González,

Sandoval-Ramírez,

Flores-Hernández

et al. 2023

CIMB

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“…In this study, out of 1.4-M compounds in the database of Vitas-M Laboratory, 0.2-M complexes were selected, transferred, and arranged through phase ( Dixon et al, 2006 ). Several groups of researchers have performed similar studies, such as for the discoveries of vaccines ( Stokes et al, 2020 ), for in silico drug repositioning for AD ( Galeana-Ascencio et al, 2023 ), and some other neurodegenerative diseases ( Ishola et al, 2021 ). Others have performed similar approaches for de novo drug design ( Wang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacophore-based virtual screening of commercial databases against β-secretase 1 for drug development against Alzheimer’s disease

Han,

Guo

2024

Front. Chem.

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β-secretase 1, one of the most important proteins, is an aspartate protease. This membrane-associated protein is used for treating Alzheimer’s disease (AD). Several inhibitors have been pursued against β-secretase 1, but they still have not resulted effectively. Virtual screening based on pharmacophores has been shown to be useful for lead optimization and hit identification in the preliminary phase of developing a new drug. Here, we screen the commercially available databases to find the hits against β-secretase 1 for drug discovery against AD. Virtual screening for 200,000 compounds was done using the database from the Vitas-M Laboratory. The phase screen score was utilized to assess the screened hits. Molecular docking was performed on compounds with phase scores >1.9. According to the study, the 66H ligand of the crystal structure has the maximum performance against β-secretase 1. The redocking of the co-crystal ligand showed that the docked ligand was seamlessly united with the crystal structure. The reference complex had three hydrogen bonds with Asp93, Asp289, and Gly291; one van der Waals interaction with Gly74; and three hydrophobic interactions. After equilibration, the RMSD of the reference compound sustained a value of ∼1.5 Å until 30 ns and then boosted to 2.5 Å. On comparison, the RMSD of the S1 complex steadily increased to ∼2.5 Å at 15 ns, displayed slight aberrations at approximately ∼2.5–3 Å until 80 ns, and then achieved steadiness toward the end of the simulation. The arrangements of proteins stayed condensed during the mockup when bonded to these complexes as stable Rg values showed. Furthermore, the MM/GBSA technique was employed to analyze both compounds’ total binding free energies (ΔGtotal). Our research study provides a new understanding of using 66H as anti-β-secretase 1 for drug development against AD.

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“…Proteins were prepared using Protein Preparation Wizard [21] according to the methodology. Molecular docking was performed on the Glide [22] module with flexibility at the site and using the ligands according to the reported protocol [12,23].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

In silico approach of 2,5-Diketopiperazines from marine organisms to neurodegenerative diseases

Rodrigo Chico-Merino,

Antonio Rosales-López,

Joel L. Terán

et al. 2024

GSC Biol. Pharm. Sci.

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In this paper we present an in silico studies of new biological active of 2,5-Diketopiperazines candidates, from Marine Organisms to neurodegenerative diseases particular for the neurodegenerative central nervous system to Alzheimer's, Huntington and Parkinson’s diseases. A total of 35 DKPs were studied, by structural similarity analysis obtained MAO-A/B, β/γ-Secretase, COX-1/2 enzymes targets obtained, to continue molecular docking studies compared to endogenous substrates and reference inhibitors, finding a multitarget potential to increase dopamine levels and decrease β-amyloid and PGE2 levels, which makes them excellent molecules for studies against neurodegenerative diseases. DKP4, DKP23 and DKP25 as inhibitors of the 6 enzymes and DKP15, DKP19, DKP21, DKP26 and DKP33 for β-Secretease specifically, the rest with multitarget potential, denoting that the DKP ring serves as a base to generate multitarget or unitarget compounds through modifications in substituents. Finally, DKPs present low bioaccumulation in the body, no toxicity, high feasibility of crossing hematoencephalic membrane and activity on the CNS, which makes them an interesting set of molecules for the search for alternatives against neurodegenerative diseases.

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β-Secretase-1: In Silico Drug Reposition for Alzheimer’s Disease

Cited by 3 publications

References 43 publications

Ginkgo biloba: Antioxidant Activity and In Silico Central Nervous System Potential

Ginkgo biloba: Antioxidant Activity and In Silico Central Nervous System Potential

Pharmacophore-based virtual screening of commercial databases against β-secretase 1 for drug development against Alzheimer’s disease

In silico approach of 2,5-Diketopiperazines from marine organisms to neurodegenerative diseases

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