Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors

Hattori, Yoshiyuki; Kobayashi, Kazuya; Deguchi, Ayaka; Nohara, Yukie; Akiyama, Tomomi; Teruya, Kenta; Sanjoh, Akira; Nakagawa, Atsushi; Yamashita, Eiki; Akaji, Kenichi

doi:10.1016/j.bmc.2015.07.023

Cited by 10 publications

(7 citation statements)

References 27 publications

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“…Analysis of Protein Data Bank [18] revealed 341 available crystal structures of human BACE but only 337 of them, including four synthetic structures (1M4H [19], 4TRW [20], 4TRY [20], 4TRZ [20]), were considered in this work since two structures were not released when the panel of proteins has been built (6EQM [21] and 6DMI [22]) and two proteins contained useless extra-domains (1UJJ [23], 1UJK [23]). Furthermore, four apo structures were found but only one was complete, namely without missing residues (1SGZ [24]).…”

Section: Protein Structuresmentioning

confidence: 99%

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

Elisée

Gapsys

Mele

et al. 2019

J Comput Aided Mol Des

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Using the D3R Grand Challenge 4 dataset containing Beta-secretase 1 (BACE) and Cathepsin S (CatS) inhibitors, we have evaluated the performance of our in-house docking workflow that involves in the first step the selection of the most suitable docking software for the system of interest based on structural and functional information available in public databases, followed by the docking of the dataset to predict the binding modes and ranking of ligands. The macrocyclic nature of the BACE ligands brought additional challenges, which were dealt with by a careful preparation of the three-dimensional input structures for ligands. This provided top-performing predictions for BACE, in contrast with CatS, where the predictions in the absence of guiding constraints provided poor results. These results highlight the importance of previous structural knowledge that is needed for correct predictions on some challenging targets. After the end of the challenge, we also carried out free energy calculations (i.e. in a non-blinded manner) for CatS using the pmx software and several force fields (AMBER, Charmm). Using knowledge-based starting pose construction allowed reaching remarkable accuracy for the CatS free energy estimates. Interestingly, we show that the use of a consensus result, by averaging the results from different force fields, increases the prediction accuracy.

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Section: Protein Structuresmentioning

confidence: 99%

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

Elisée

Gapsys

Mele

et al. 2019

J Comput Aided Mol Des

View full text Add to dashboard Cite

show abstract

“…Therefore, the classic steady-state or rapid-equilibrium rate equations for inhibition mechanisms are no longer applicable . A number of reports in the literature fit inhibition data using simple dose–response curves to estimate IC 50 values. , However, IC 50 values can vary significantly depending on the assay conditions and analysis methods used. Therefore, it is better to determine the K i values for compounds since they are true equilibrium dissociation constants instead of determining IC 50 values which are less reliable.…”

Section: Resultsmentioning

confidence: 99%

Development of an Efficient Enzyme Production and Structure-Based Discovery Platform for BACE1 Inhibitors

et al. 2019

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BACE1 (Beta-site Amyloid Precursor Protein (APP) Cleaving Enzyme 1) is a promising therapeutic target for Alzheimer’s Disease (AD). However, efficient expression, purification, and crystallization systems are not well described or detailed in the literature nor are approaches for treatment of enzyme kinetic data for potent inhibitors well described. We therefore developed a platform for expression and purification of BACE1, including protein refolding from E.coli inclusion bodies, in addition to optimizing a reproducible crystallization procedure of BACE1 bound with inhibitors. We also report a detailed approach to the proper analysis of enzyme kinetic data for compounds that exhibit either rapid-equilibrium or tight-binding mechanisms. Our methods allow for the purification of ∼15 mg of BACE1 enzyme from 1 L of culture which is higher than reported yields in the current literature. To evaluate the data analysis approach developed here, a well-known potent inhibitor and two of its derivatives were tested, analyzed, and compared. The inhibitory constants (K i) obtained from the kinetic studies are in agreement with dissociation constants (K d) that were also determined using isothermal titration calorimetry (ITC) experiments. The X-ray structures of these three compounds in complex with BACE1 were readily obtained and provide important insight into the structure and thermodynamics of the BACE1-inhibitor interactions.

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“…There is no information about BACE1 inhibitors (BACE1-I) with the heterocyclic system pyrazolo [3,4-b] quinolin-5-one; therefore, it would be interesting to study this family of compounds as BACE1-I. Several inhibitors of this enzyme have different aromatic systems, to mention some, phenyl (Panek et al, 2018), thiophene (Hattori et al, 2015), furan (Cherukury et al, 2016), which are structurally related to the seed (29) used in this work, pyrazole (Zou et al, 2013) and quinoline (Najafi et al, 2016).…”

Section: Design Of New Bace1 Inhibitorsmentioning

confidence: 99%

Bennett acceptance ratio method to calculate the binding free energy of BACE1 inhibitors: Theoretical model and design of new ligands of the enzyme

et al. 2019

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In recent years, the design, development, and evaluation of several inhibitors of the BACE1 enzyme, as part of Alzheimer's treatment, have gathered the scientific community's interest. Here, a linear regression model was built using binding free energy calculations through the Bennett acceptance ratio method for 20 known inhibitors of the BACE1 enzyme, with a Pearson coefficient of R = 0.88 and R2 = 0.78. The validation of this model was verified employing eight additional random inhibitors, which also gave a linear correlation with R = 0.97 and R2 = 0.93. Furthermore, this linear regression model was also used for proposing the structure of four potential BACE1 inhibitors, and the most active of them gave a theoretical Kd = 10 nM. However, these molecules have not been synthesized yet. Our team used a total time of more than 800 ns for the Molecular Dynamics to carry out this study, and all the software used were freely available.

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Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors

Cited by 10 publications

References 27 publications

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

Development of an Efficient Enzyme Production and Structure-Based Discovery Platform for BACE1 Inhibitors

Bennett acceptance ratio method to calculate the binding free energy of BACE1 inhibitors: Theoretical model and design of new ligands of the enzyme

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