Binding modes and conformational changes of FK506-binding protein 51 induced by inhibitor bindings: insight into molecular mechanisms based on multiple simulation technologies

Chen, Jianzhong; Yin, Baohua; Pang, Laixue; Wang, Wei; Zhang, John Z. H.

doi:10.1080/07391102.2019.1624616

Cited by 16 publications

(5 citation statements)

References 94 publications

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“…PC analysis and cross-correlation analysis were carried out based on the single joined aMD trajectory using the CPPTRAJ module 92 in Amber, and the details have been provided in our previous works. 93,94 MM-GBSA Calculations. Molecular mechanics Poisson−Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA) methods are thought to be two efficient approaches for rapidly computing binding free energies.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations

Chen

Yin

Wang

et al. 2020

ACS Chem. Neurosci.

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The β-amyloid cleaving enzyme 1 (BACE1) has been thought to be an efficient target for treatment of Alzheimer’s disease (AD). Deep insight into inhibitor–BACE1 binding mechanism is of significance for design of potent drugs toward BACE1. In this work, multiple replica accelerated molecular dynamics (MR-aMD) simulations, principal component (PC) analysis, and free energy landscapes were integrated to decode the effect of disulfide bonds (SSBs) in BACE1 on bindings of three inhibitors 3KO, 3KT, and 779 to BACE1. The results from cross-correlation analysis suggest that the breaking of SSBs exerts significant influence on structural flexibility and internal dynamics of inhibitor-bound BACE1. PC analysis and free energy landscapes reveal that the breaking of SSBs not only evidently induces the conformational rearrangement of BACE1 but also highly changes binding poses of three inhibitors in BACE1 and leads to more disordered binding of three inhibitors to BACE1, which is further supported by the increase in binding entropy of inhibitors to BACE1 due to the breaking of SSBs. Residue-based free energy decomposition method was utilized to evaluate contributions of separate residues to inhibitor–BACE1 binding. The results suggest that although the breaking of SSBs in BACE1 does not destroy the interaction network of inhibitors with BACE1 it changes interaction strength of some residues with inhibitors. Meanwhile, the information from residue-based free energy decomposition indicates that residues L91, S96, V130, Y132, Q134, W137, F169, I171, and I179 can be used as efficient targets of drug design toward BACE1.

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Section: ■ Materials and Methodsmentioning

confidence: 99%

“…All simulations were run by making use of the program pmemd.cuda implemented in Amber. PC analysis and cross-correlation analysis were carried out based on the single joined aMD trajectory using the CPPTRAJ module in Amber, and the details have been provided in our previous works. , …”

Section: Materials and Methodsmentioning

confidence: 99%

Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations

Chen

Yin

Wang

et al. 2020

ACS Chem. Neurosci.

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“…These three structures were minimized to remove bad contacts between atoms. For the current docking, the grid box in (x, y, z) direction was set to (60,60,60) Å with a spacing value of 0.375 Å. The docking was carried out by using the Lamarckian genetic algorithm (LGA) and the parameters used during docking were set as the default values of the software.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…More importantly, these two methods have been applied to successfully explore the binding selectivity of the inhibitors toward homologous proteins with high sequence identity. − However, the conformations sampled by cMD simulations possibly fall into a locally minimal space, which will lead to an insufficient conformational sampling. The previous literatures indicated that multiple short MD (MSMD) simulations can better sample on conformations of receptors than a single long MD simulation. − Thus, MSMD simulations were adopted to perform rationally conformational samplings on BACE1 and BACE2 so as to reliably investigate binding selectivity of inhibitors to these two proteins. To realize our aim, three inhibitors DBO, CS9, and SC7 were selected for current studies.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions

Chen

Wang

Yin

et al. 2019

ACS Chem. Neurosci.

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The β-amyloid cleaving enzymes 1 and 2 (BACE1 and BACE2) have been regarded as the prospective targets for clinically treating Alzheimer's disease (AD) in the last two decades. Thus, insight into the binding differences of inhibitors to BACE1 and BACE2 is of significance for designing highly selective inhibitors toward the two proteins. In this work, multiple short molecular dynamics (MSMD) simulations are coupled with the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding selectivity of three inhibitors DBO, CS9, and SC7 on BACE1 over BACE2. The results show that the entropy effect plays a key role in selectivity identification of inhibitors toward BACE1 and BACE2, which determines that DBO has better selectivity toward BACE2 over BACE1, while CS9 and CS7 can more favorably bind to BACE1 than BACE2. The hierarchical clustering analysis based on energetic contributions of residues suggests that BACE1 and BACE2 share the common hot interaction spots. The residue-based free-energy decomposition method was applied to compute the inhibitor−residue interaction spectrum, and the results recognize four common binding subpockets corresponding to the different groups of inhibitors, which can be used as efficient targets for designing highly selective inhibitors toward BACE1 and BACE2. Therefore, these results provide a useful molecular basis and dynamics information for development of highly selective inhibitors targeting BACE1 and BACE2.

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“…All known advanced FKBP51-selective ligands, including the widely used SAFit2 and newly developed macrocycles, use a cyclohexyl group as the Phe67 out -stabilizing moiety (crucial for selectivity) and a D 68 /S 118 /K 122 -targeting trialkoxyaryl moiety to achieve potency (Figure ). − Especially the cyclohexyl group was shown to be very sensitive to minor modifications, and despite substantial efforts, all attempts to replace this group were not met with success. ,, …”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of a New Selectivity-Enabling Motif for the FK506-Binding Protein 51

et al. 2023

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In recent years, the selective inhibition of FKBP51 has emerged as a possible treatment for chronic pain, obesityinduced diabetes, or depression. All currently known advanced FKBP51-selective inhibitors, including the widely used SAFit2, contain a cyclohexyl residue as a key motif for enabling selectivity over the closest homologue and anti-target FKBP52. During a structure-based SAR exploration, we surprisingly discovered thiophenes as highly efficient cyclohexyl replacement moieties that retain the strong selectivity of SAFit-type inhibitors for FKBP51 over FKBP52. Cocrystal structures revealed that the thiophenecontaining moieties enable selectivity by stabilizing a flipped-out conformation of Phe 67 of FKBP51. Our best compound, 19b, potently binds to FKBP51 biochemically as well as in mammalian cells, desensitize TRPV1 in primary sensory neurons, and has an acceptable PK profile in mice, suggesting its use as a novel tool compound for studying FKBP51 in animal models of neuropathic pain.

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Binding modes and conformational changes of FK506-binding protein 51 induced by inhibitor bindings: insight into molecular mechanisms based on multiple simulation technologies

Cited by 16 publications

References 94 publications

Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations

Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations

Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions

Structure-Based Discovery of a New Selectivity-Enabling Motif for the FK506-Binding Protein 51

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