Computational insights into the protonation states of catalytic dyad in BACE1–acyl guanidine based inhibitor complex

Kocak, Abdulkadır; Erol, İsmail; Yıldız, Müslüm; Can, Hatıce Kaplan

doi:10.1016/j.jmgm.2016.10.013

Cited by 36 publications

(25 citation statements)

References 42 publications

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“…However, the protonation status of the dyad while the inhibitor is in place is not well established. Kocak et al investigated all the possible protonation status of the dyad amino acids in the presence of potent acyl guanidine‐based inhibitor, with the aim to determine the most stable and favorable protonation status . The results of molecular dynamic simulations showed that when the ligand‐containing NH 2 warhead is protonated (at pH 4.5), the di‐deprotonated status of the dyad is the most preferred, and is 14 kcal/mole more stable than all other presumed options .…”

Section: Failure Of Bace1 Inhibitors: Lessons To the Futurementioning

confidence: 99%

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

211

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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Section: Failure Of Bace1 Inhibitors: Lessons To the Futurementioning

confidence: 99%

“…A similar positive finding was confirmed when the ligand was unprotonated. Thus, one should consider the protonation status, when designing BACE1 inhibitors, since it might be a pivotal player to stabilize their interaction with the enzyme …”

Section: Failure Of Bace1 Inhibitors: Lessons To the Futurementioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

211

175

View full text Add to dashboard Cite

show abstract

“…Previous studies have attempted to use constant pH 17,18 or other forms of MD 19,[22][23][24][25][26] to study BACE-1 dynamics. To our knowledge, this is the first study to use explicit solvent CpH-MD to quantitatively examine the effect of pH on water lifetimes in BACE-1 and to attempt to correlate this with a conformational change in the protein towards the understanding of the source of the pH dependence of BACE-1 activity.…”

Section: Previous Work By Kim Et Al 17 As Well As Ellis and Shen 18 Bothmentioning

confidence: 99%

“…By accounting explicitly for the possibility of multiple protonation states, we can vastly improve our understanding of pH‐dependent conformational changes and the associated changes in electrostatic environment. Previous studies have attempted to use constant pH or other forms of MD to study BACE‐1 dynamics. To our knowledge, this is the first study to use explicit solvent CpH‐MD to quantitatively examine the effect of pH on water lifetimes in BACE‐1 and to attempt to correlate this with a conformational change in the protein towards the understanding of the source of the pH dependence of BACE‐1 activity.…”

Section: Introductionmentioning

confidence: 99%

pH‐dependent conformational dynamics of beta‐secretase 1: A molecular dynamics study

Mermelstein

McCammon

Walker

2018

J of Molecular Recognition

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Beta‐secretase 1 (BACE‐1) is an aspartyl protease implicated in the overproduction of β‐amyloid fibrils responsible for Alzheimer disease. The process of β‐amyloid genesis is known to be pH dependent, with an activity peak between solution pH of 3.5 and 5.5. We have studied the pH‐dependent dynamics of BACE‐1 to better understand the pH dependent mechanism. We have implemented support for graphics processor unit (GPU) accelerated constant pH molecular dynamics within the AMBER molecular dynamics software package and employed this to determine the relative population of different aspartyl dyad protonation states in the pH range of greatest β‐amyloid production, followed by conventional molecular dynamics to explore the differences among the various aspartyl dyad protonation states. We observed a difference in dynamics between double‐protonated, mono‐protonated, and double‐deprotonated states over the known pH range of higher activity. These differences include Tyr 71‐aspartyl dyad proximity and active water lifetime. This work indicates that Tyr 71 stabilizes catalytic water in the aspartyl dyad active site, enabling BACE‐1 activity.

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“…Besides, the crystallization water molecules, the crystallization dimer, and the inhibitor were removed. The aspartate residue 32 (ASP32) was modified into its protonated state (ASH32) (Cheron & Shakhnovich, ; Kocak, Erol, Yildiz, & Can, ; Polgár & Keserü, ) by the force field Amber03 (Duan et al., ).…”

Section: Methodsmentioning

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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Computational insights into the protonation states of catalytic dyad in BACE1–acyl guanidine based inhibitor complex

Cited by 36 publications

References 42 publications

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

pH‐dependent conformational dynamics of beta‐secretase 1: A molecular dynamics study

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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