ArticleJournal of computational chemistry2017
Conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor.
Article in Journal of computational chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 22 citations in OpenAlex.
- Exploring the pH- and Ligand-Dependent Flap Dynamics of Malarial Plasmepsin II.Journal of chemical information and modeling · 2022Article
- A Guide to the Continuous Constant pH Molecular Dynamics Methods in Amber and CHARMM [Article v1.0].Living journal of computational molecular science · 2022Article
- Cathepsin D-Managing the Delicate Balance.Pharmaceutics · 2021Review
- Exploring the pH-Dependent Structure-Dynamics-Function Relationship of Human Renin.Journal of chemical information and modeling · 2021Article
- Is It the Twilight of BACE1 Inhibitors?Current neuropharmacology · 2021Article
- Catalytic Site pJournal of chemical information and modeling · 2020Article
- GPU-Accelerated Implementation of Continuous Constant pH Molecular Dynamics in Amber: pJournal of chemical information and modeling · 2019Article
- How Electrostatic Coupling Enables Conformational Plasticity in a Tyrosine Kinase.Journal of the American Chemical Society · 2019Article
- Predicting Catalytic Proton Donors and Nucleophiles in Enzymes: How Adding Dynamics Helps Elucidate the Structure-Function Relationships.The journal of physical chemistry letters · 2018Article
- Proton-Coupled Conformational Allostery Modulates the Inhibitor Selectivity for β-Secretase.The journal of physical chemistry letters · 2017Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
BACE1 is a major therapeutic target for prevention and treatment of Alzheimer's disease. Developing inhibitors that can selectively target BACE1 in favor of other proteases, especially cathepsin D (CatD), has presented significant challenges. Here, we investigate the conformational dynamics and protonation states of BACE1 and CatD using continuous constant pH molecular dynamics with pH replica-exchange sampling protocol. Despite similar structure, BACE1 and CatD exhibit markedly different active site dynamics. BACE1 displays pH-dependent flap dynamics that controls substrate accessibility, while the CatD flap is relatively rigid and remains open in the pH range 2.5-6. Interestingly, although each protease hydrolyzes peptide bonds, the protonation states of the catalytic dyads are different within the active pH range. The acidic and basic components of the BACE1 catalytic dyad are clear, while either aspartic acid of the CatD catalytic dyad could play the role of acid or base. Finally, we investigate binding of the inhibitor LY2811376 developed by Eli Lilly to BACE1 and CatD. Surprisingly, in the enzyme active pH range, LY2811376 forms a stronger salt bridge with the catalytic dyad in CatD than in BACE1, which might explain the retinal toxicity of the inhibitor related to off-target inhibition of CatD. This work highlights the complexity and challenge in structure-based drug design where receptor-ligand binding induces protonation state change in both the protein and the inhibitor. © 2017 Wiley Periodicals, Inc.
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