Identification of potential human beta-secretase 1 inhibitors by hierarchical virtual screening and molecular dynamics

Bomfim, Mayra Ramos do; Barbosa, Deyse Brito; Carvalho, Paulo; Silva, Alisson Marques da; Oliveira, Tiago Alves de; Taranto, Alex Gutterres; Leite, Franco Henrique Andrade

doi:10.1080/07391102.2022.2069155

Cited by 5 publications

(8 citation statements)

References 78 publications

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“…Validation methods were used, and after obtaining the data, the program selected for molecular docking with BACE-1 was GOLD 5.8.1 [ 27 , 28 ]. The score was provided by the Astex Scoring Potential (ASP, knowledge-based function derived from a database of protein–ligand complexes) function with the parameters previously validated [ 29 ]. The search parameters were evaluated for the ability to identify the crystallographic pose through redocking with the better pose according to root-mean-square deviation (RMSD < 2 Å) and asset recognition capability against false positives by calculating the area under the ROC curve (AUC > 0.7) [ 25 , 29 ].…”

Section: Methodsmentioning

confidence: 99%

Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and β-Secretase 1: Next Generation for Alzheimer’s Disease Treatment

et al. 2023

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Alzheimer’s Disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other affected cognitive functions. Pharmacological therapy of AD relies on inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), offering only a palliative effect and being incapable of stopping or reversing the neurodegenerative process. However, recent studies have shown that inhibiting the enzyme β-secretase 1 (BACE-1) may be able to stop neurodegeneration, making it a promising target. Considering these three enzymatic targets, it becomes feasible to apply computational techniques to guide the identification and planning of molecules capable of binding to all of them. After virtually screening 2119 molecules from a library, 13 hybrids were built and further screened by triple pharmacophoric model, molecular docking, and molecular dynamics (t = 200 ns). The selected hybrid G meets all stereo-electronic requirements to bind to AChE, BChE, and BACE-1 and offers a promising structure for future synthesis, enzymatic testing, and validation.

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Section: Methodsmentioning

confidence: 99%

Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and β-Secretase 1: Next Generation for Alzheimer’s Disease Treatment

et al. 2023

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“…AutoDock Vina, selected for molecular docking to AChE and BChE [7], scores structures by mapping intermolecular forces in kcal/mol, with lower energy indicating better docking. GOLD (ASP score function) was selected for molecular docking to BACE-1 [18]. It assigns a dimensionless number to each pose generated, and unlike AutoDock Vina, higher numbers indicate better docking.…”

Section: Molecular-docking-based Virtual Screeningmentioning

confidence: 99%

“…The BACE-1 crystallographic ligand (Figure 7) forms hydrogen bonds with TRP76, ASP32, ASP228, and GLY230 and hydrophobic interactions with LEU30, VAL69, TYR71, ILE118, and ARG128 [18]. Figure 8 shows the analysis of the complexes generated between BACE-1 and ZINC45068352, ZINC03873986, and ZINC71787288.…”

Section: Bace-1 Complexesmentioning

confidence: 99%

“…As for the BACE-1 structure, the receptor had its protonation state evaluated by the H++ 1.0 server [http://newbiophysics.cs.vt.edu/H++/ accessed on 24 September 2020] program, and pKa was corrected at pH 4.5 [45]. Validation methods were used, and the program selected for molecular docking with BACE-1 was GOLD 5.8.1 [46]; the score was provided by the Astex Scoring Potential (ASP, knowledgebased function derived from a database of protein-ligand complexes) function with the parameters previously validated [18].…”

Section: Molecular Dockingmentioning

confidence: 99%

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Identification of Potential Multitarget Compounds against Alzheimer’s Disease through Pharmacophore-Based Virtual Screening

Mendes,

Araújo Neto,

Barbosa

et al. 2023

Pharmaceuticals

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of cognitive functions, and it is the most prevalent type of dementia worldwide, accounting for 60 to 70% of cases. The pathogenesis of AD seems to involve three main factors: deficiency in cholinergic transmission, formation of extracellular deposits of β-amyloid peptide, and accumulation of deposits of a phosphorylated form of the TAU protein. The currently available drugs are prescribed for symptomatic treatment and present adverse effects such as hepatotoxicity, hypertension, and weight loss. There is urgency in finding new drugs capable of preventing the progress of the disease, controlling the symptoms, and increasing the survival of patients with AD. This study aims to present new multipurpose compounds capable of simultaneously inhibiting acetylcholinesterase (AChE), butyrylcholinesterase (BChE)—responsible for recycling acetylcholine in the synaptic cleft—and beta-secretase 1 (BACE-1)—responsible for the generation of amyloid-β plaques. AChE, BChE, and BACE-1 are currently considered the best targets for the treatment of patients with AD. Virtual hierarchical screening based on a pharmacophoric model for BACE-1 inhibitors and a dual pharmacophoric model for AChE and BChE inhibitors were used to filter 214,446 molecules by QFITBACE > 0 and QFITDUAL > 56.34. The molecules selected in this first round were subjected to molecular docking studies with the three targets and further evaluated for their physicochemical and toxicological properties. Three structures: ZINC45068352, ZINC03873986, and ZINC71787288 were selected as good fits for the pharmacophore models, with ZINC03873986 being ultimately prioritized for validation through activity testing and synthesis of derivatives for SAR studies.

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“…A validated method [30] was used to evaluate the interactions of ligands cholinesterases, showing the efficiency of the Auto-Dock Vina 1.1.2 program fo enzymes (RMSDAChE = 1.97 Å/AUCAChE = 0.88 and RMSDBuChE = 1.77 Å/AUCBuChE The tests with BACE-1 were conducted using the GOLD 5.8.1 program with t scoring function (RMSD = 1.13 Å/AUC = 0.78) [33]. Compounds presenting an value smaller than the average of the calculated energies compared to choline (AChE < −7.95 kcal/mol and BuChE < −4.60 kcal/mol) and higher than the averag scores calculated for BACE-1 (>37.8) (n = 12) were considered to have the bes inhibition profile and selected for the prediction of toxicological and pharmaco parameters.…”

Section: Hierarchical Virtual Screeningmentioning

confidence: 99%

Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach

Barbosa,

do Bomfim,

de Oliveira

et al. 2023

Pharmaceuticals

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Alzheimer’s disease causes chronic neurodegeneration and is the leading cause of dementia in the world. The causes of this disease are not fully understood but seem to involve two essential cerebral pathways: cholinergic and amyloid. The simultaneous inhibition of AChE, BuChE, and BACE-1, essential enzymes involved in those pathways, is a promising therapeutic approach to treat the symptoms and, hopefully, also halt the disease progression. This study sought to identify triple enzymatic inhibitors based on stereo-electronic requirements deduced from molecular modeling of AChE, BuChE, and BACE-1 active sites. A pharmacophore model was built, displaying four hydrophobic centers, three hydrogen bond acceptors, and one positively charged nitrogen, and used to prioritize molecules found in virtual libraries. Compounds showing adequate overlapping rates with the pharmacophore were subjected to molecular docking against the three enzymes and those with an adequate docking score (n = 12) were evaluated for physicochemical and toxicological parameters and commercial availability. The structure exhibiting the greatest inhibitory potential against all three enzymes was subjected to molecular dynamics simulations (100 ns) to assess the stability of the inhibitor-enzyme systems. The results of this in silico approach indicate ZINC1733 can be a potential multi-target inhibitor of AChE, BuChE, and BACE-1, and future enzymatic assays are planned to validate those results.

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Identification of potential human beta-secretase 1 inhibitors by hierarchical virtual screening and molecular dynamics

Cited by 5 publications

References 78 publications

Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and β-Secretase 1: Next Generation for Alzheimer’s Disease Treatment

Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and β-Secretase 1: Next Generation for Alzheimer’s Disease Treatment

Identification of Potential Multitarget Compounds against Alzheimer’s Disease through Pharmacophore-Based Virtual Screening

Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational Approach

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