Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

Wu, Yong‐Jin; Guernon, Jason; Yang, Fan; Snyder, Lawrence B.; Shi, Jun; McClure, Andrea; Rajamani, Ramkumar; Park, Hyunsoo; Ng, Alicia; Lewis, H.A.; Chang, ChiehYing Y.; Camac, Dan; Toyn, Jeremy H.; Ahlijanian, Michael K.; Albright, Charles F.; Macor, John E.; Thompson, Lorin A.

doi:10.1021/acsmedchemlett.5b00432

Cited by 31 publications

(31 citation statements)

References 16 publications

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“…The docking analysis represented that both two compounds interacted with the second water binding site of BACE1, where lupeol showed strong hydrophobic interactions with the flap region. These results demonstrated the inhibition mechanism of lupeol and ursolic acid, which are also consistent with the previously published docking results [23,[40][41][42][43][44][45]. Subsequently, the binding free energies of two complexes have been analyzed by MM-GBSA and MM/GBVI methods, and in both cases, lupeol showed better binding energies than ursolic acid.…”

Section: Discussionsupporting

confidence: 90%

Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Hosen

Rubayed

Dash

et al. 2019

CPD

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Alzheimer disease (AD) can be considered the most common age-related neurodegenerative disorder, and also, an important cause of death in elderly patients. A number of studies found the correlation of this disease pathology with BACE1 inhibitor and it is also evident that BACE1 inhibitor can function as a very potent treatment strategy in treating AD. In the present study, we aimed to prospect for novel plant-derived BACE1 inhibitors from Leea indica and to realize the structural basis of their interactions and mechanisms using combined molecular docking and molecular dynamics based approaches. An extensive library of Leea indica plant-derived molecule was compiled and computationally screened for inhibitory action against BACE1 by using virtual screening approaches. Furthermore, induced fit docking and classical molecular dynamics along with steered molecular dynamics simulations were employed to get insight the binding mechanisms. Two triterpenoids, ursolic acid and lupeol were identified through virtual screening; wherein, lupeol showed better binding free energy in MM/GBSA, MM/PBSA and MM/GBVI approaches. Furthermore classical and steered dynamics revealed the favourable hydrophobic interactions between the lupeol and the residues of flap or catalytic dyad of BACE1; however, ursolic acid showed disfavorable interactions with the BACE1. This study, therefore, unveiled the lupeol as a potent BACE1 inhibitor from a manually curated dataset of Leea indica molecules, which may provide a new dimension of designing novel BACE1 inhibitors for AD therapy.

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Section: Discussionsupporting

confidence: 90%

Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Hosen

Rubayed

Dash

et al. 2019

CPD

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“…By fitting the pharmacophore against MBM, BACE1 was picked out as a HPT for berberine with a value of 0.788156 ( Table 1 ). The complex of BACE1 with compound 10 (5ENM) was calculated using force field CHARMm which showed the binding energy to be -110.2 kcal/mol ( Wu et al, 2016 ). The docked complex of BACE1 with berberine was more structurally stable and energetically favorable than the compound 10, with the binding energy reaching to -123.6 kcal/mol.…”

Section: Resultsmentioning

confidence: 99%

Polypharmacology of Berberine Based on Multi-Target Binding Motifs

et al. 2018

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Background: Polypharmacology is emerging as the next paradigm in drug discovery. However, considerable challenges still exist for polypharmacology modeling. In this study, we developed a rational design to identify highly potential targets (HPTs) for polypharmacological drugs, such as berberine.Methods and Results: All the proven co-crystal structures locate berberine in the active cavities of a redundancy of aromatic, aliphatic, and acidic residues. The side chains from residues provide hydrophobic and electronic interactions to aid in neutralization for the positive charge of berberine. Accordingly, we generated multi-target binding motifs (MBM) for berberine, and established a new mathematical model to identify HPTs based on MBM. Remarkably, the berberine MBM was embodied in 13 HPTs, including beta-secretase 1 (BACE1) and amyloid-β1-42 (Aβ1-42). Further study indicated that berberine acted as a high-affinity BACE1 inhibitor and prevented Aβ1-42 aggregation to delay the pathological process of Alzheimer’s disease.Conclusion: Here, we proposed a MBM-based drug-target space model to analyze the underlying mechanism of multi-target drugs against polypharmacological profiles, and demonstrated the role of berberine in Alzheimer’s disease. This approach can be useful in derivation of rules, which will illuminate our understanding of drug action in diseases.

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“…Recent BACE1 inhibitors that were developed using CADD will be summarized in this section. In silico structure-based design was extensively employed in the development of BACE1 inhibitors including the discovery of peptides with a 5-fluoroorotyl moiety [37], 5,5 -disubstituted aminohydantoins [38], bicyclic iminopyrimidinones [39], iminopyrimidinones [40], cyclic sulfone hydroxyethylamines [41], imidazopyridines containing isoindoline-1,3-dione [42], iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole [43], 2-substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamide derivatives [44], cyclopropane-based conformationally restricted analogues [45], 6-dimethylisoxazole-substituted biaryl aminothiazines [46], and other compounds [47]. In these studies, a combination of molecular docking, X-ray crystallography, synthesis, and in vitro testing was utilized to develop potent BACE1 inhibitors.…”

Section: Cadd For the Development Of Bace1 Inhibitorsmentioning

confidence: 99%

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

Mouchlis

Melagraki

Zacharia

et al. 2020

IJMS

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Aging-associated neurodegenerative diseases, which are characterized by progressive neuronal death and synapses loss in human brain, are rapidly growing affecting millions of people globally. Alzheimer’s is the most common neurodegenerative disease and it can be caused by genetic and environmental risk factors. This review describes the amyloid-β and Tau hypotheses leading to amyloid plaques and neurofibrillary tangles, respectively which are the predominant pathways for the development of anti-Alzheimer’s small molecule inhibitors. The function and structure of the druggable targets of these two pathways including β-secretase, γ-secretase, and Tau are discussed in this review article. Computer-Aided Drug Design including computational structure-based design and ligand-based design have been employed successfully to develop inhibitors for biomolecular targets involved in Alzheimer’s. The application of computational molecular modeling for the discovery of small molecule inhibitors and modulators for β-secretase and γ-secretase is summarized. Examples of computational approaches employed for the development of anti-amyloid aggregation and anti-Tau phosphorylation, proteolysis and aggregation inhibitors are also reported.

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Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

Cited by 31 publications

References 16 publications

Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Prospecting and Structural Insight into the Binding of Novel Plant-Derived Molecules of Leea indica as Inhibitors of BACE1

Polypharmacology of Berberine Based on Multi-Target Binding Motifs

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

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