ArticleThe journal of physical chemistry letters2016
Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors.
Article in The journal of physical chemistry letters, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 54 citations in OpenAlex.
- Enhanced and Efficient Predictions of Dynamic Ionization through Constant-pH Adiabatic Free Energy Dynamics.Journal of chemical theory and computation · 2024Article
- Impact of protein conformations on binding free energy calculations in the beta-secretase 1 system.Journal of computational chemistry · 2024Article
- Rapid Rescoring and Refinement of Ligand-Receptor Complexes Using Replica Exchange Molecular Dynamics with a Monte Carlo Pose Reservoir.Journal of chemical theory and computation · 2023Article
- Identification Mechanism of BACE1 on Inhibitors Probed by Using Multiple Separate Molecular Dynamics Simulations and Comparative Calculations of Binding Free Energies.Molecules (Basel, Switzerland) · 2023Article
- Biologically relevant small variations of intra-cellular pH can have significant effect on stability of protein-DNA complexes, including the nucleosome.Frontiers in molecular biosciences · 2023Article
- Novel US-CpHMD Protocol to Study the Protonation-Dependent Mechanism of the ATP/ADP Carrier.Journal of chemical information and modeling · 2022Article
- Addressing Intersite Coupling Unlocks Large Combinatorial Chemical Spaces for Alchemical Free Energy Methods.Journal of chemical theory and computation · 2022Article
- 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
- Continuous Constant pH Molecular Dynamics Simulations of Transmembrane Proteins.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Assessment of proton-coupled conformational dynamics of SARS and MERS coronavirus papain-like proteases: Implication for designing broad-spectrum antiviral inhibitors.The Journal of chemical physics · 2020Article
- Scalable molecular dynamics on CPU and GPU architectures with NAMD.The Journal of chemical physics · 2020Article
- D3R Grand Challenge 4: ligand similarity and MM-GBSA-based pose prediction and affinity ranking for BACE-1 inhibitors.Journal of computer-aided molecular design · 2020Article
- Allosteric discrimination at the NADH/ADP regulatory site of glutamate dehydrogenase.Protein science : a publication of the Protein Society · 2019Article
- Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4.Journal of computer-aided molecular design · 2019Article
- 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
- Dynamic Protonation Dramatically Affects the Membrane Permeability of Drug-like Molecules.Journal of the American Chemical Society · 2019Article
- How Ligand Protonation State Controls Water in Protein-Ligand Binding.The journal of physical chemistry letters · 2018Article
- Factors Influencing the Potency of Alzheimer Inhibitors: Computational and Docking Studies.American journal of Alzheimer's disease and other dementias · 2018Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Targeting β-secretase (BACE1) with small-molecule inhibitors offers a promising route for treatment of Alzheimer's disease. However, the intricate pH dependence of BACE1 function and inhibitor efficacy has posed major challenges for structure-based drug design. Here we investigate two structurally similar BACE1 inhibitors that have dramatically different inhibitory activity using continuous constant pH molecular dynamics (CpHMD). At high pH, both inhibitors are stably bound to BACE1; however, within the enzyme active pH range, only the iminopyrimidinone-based inhibitor remains bound, while the aminothiazine-based inhibitor becomes partially dissociated following the loss of hydrogen bonding with the active site and change of the 10s loop conformation. The drastically lower activity of the second inhibitor is due to the protonation of a catalytic aspartate and the lack of a propyne tail. This work demonstrates that CpHMD can be used for screening pH-dependent binding profiles of small-molecule inhibitors, providing a new tool for structure-based drug design and optimization.
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