Enhancing Drug Residence Time by Shielding of Intra-Protein Hydrogen Bonds: A Case Study on CCR2 Antagonists

Magarkar, Aniket; Schnapp, Gisela; Apel, Anna-Katharina; Seeliger, Daniel; Tautermann, Christofer S.

doi:10.1021/acsmedchemlett.8b00590

Cited by 15 publications

(10 citation statements)

References 32 publications

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“…B) suggests a rearrangement of the hydrogen bond network that led to changes in the residence time . This is supported by subsequent MD simulations, which show that the residence time for MK‐0812 and structurally related ligands is directly dependent on the shielding of the Y120 3.32 ‐ E291 7.39 H‐bond from the water .…”

Section: Comparison and Implications Of Ccr2 Structuresmentioning

confidence: 59%

In situ crystallography as an emerging method for structure solution of membrane proteins: the case of CCR2A

Cheng¹,

Huang

Hennig³

et al. 2019

The FEBS Journal

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The in meso in situ serial X‐ray crystallization method (Huang et al., (2015) Acta Crystallogr D Biol Crystallogr 71, 1238) combines lipid cubic phase crystallization, direct freezing of the crystallization droplet without handling of the crystals, and data collection in situ. Recently, this method was used to overcome the mechanical fragility of crystals which enabled the X‐ray structure determination of chemokine receptor 2A (Apel et al., (2019) Structure 27, 427) at 2.7 Å resolution. The CCR2 structure provides the structural basis for ligand selectivity of CCR2 against chemokine receptor 5 and provides insights into the residence time of MK‐0812 analogs based on molecular dynamics simulations. These findings offer new opportunities for drug discovery targeting chemokine receptors.

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Section: Comparison and Implications Of Ccr2 Structuresmentioning

confidence: 59%

In situ crystallography as an emerging method for structure solution of membrane proteins: the case of CCR2A

Cheng¹,

Huang

Hennig³

et al. 2019

The FEBS Journal

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“…Apart from the role of pulling the IgV domain back to nivolumab, the N-terminal loop may also increase the nivolumab residence time by shielding the IgV-nivolumab H-bonds from water. In previously reported studies, the relationship between long residence time and accessibility of water has been established ( Schmidtke et al, 2011 ; Magarkar et al, 2019 ). In this study, binding of the N-terminal loop with nivolumab can create an environment of lower dielectric constant around the BC loop, shielded from bulk solvent ( Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

Investigating the Role of the N-Terminal Loop of PD-1 in Binding Process Between PD-1 and Nivolumab via Molecular Dynamics Simulation

Liu

Jin

Chen

et al. 2020

Front. Mol. Biosci.

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The blockade of immune checkpoints, such as programmed death receptor 1 (PD-1) and programmed death ligand 1 protein (PD-L1), is a promising therapeutic approach in cancer immunotherapy. Nivolumab, a humanized IgG4 antibody targeting PD-1, was approved by the US Food and Drug Administration for several cancers in 2014. Crystal structures of the nivolumab/PD-1 complex show that the epitope of PD-1 locates at the IgV domain (including the FG and BC loops) and the N-terminal loop. Although the N-terminal loop of PD-1 has been shown to play a dominant role in the complex interface of the static structure, its role in the dynamic binding process has not been illustrated clearly. Here, eight molecular systems were established for nivolumab/PD-1 complex, and long-time molecular dynamics simulations were performed for each. Results showed that the N-terminal loop of PD-1 prefers to bind with nivolumab to stabilize the interface between IgV and nivolumab. Furthermore, the binding of the N-terminal loop with nivolumab induces the rebinding between the IgV domain and nivolumab. Thus, we proposed a two-step binding model for the nivolumab/PD-1 binding, where the interface switches to a high-affinity state with the help of the N-terminal loop. This finding suggests that the N-terminal loop of PD-1 might be a potential target for anti-PD-1 antibody design, which could serve as an important gatekeeper for the anti-PD-1 antibody binding.

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“…For example, Schmidtke et al showed that shielding ligand-receptor hydrogen bonds from water can contribute to long ligand residence time [ 87 ]. Interestingly, Magarkar et al recently found, based on MD simulations, that shielding of water from intra-protein interactions, not directly involved in ligand−receptor interactions, is also a relevant factor in ligand binding kinetics, as such interactions confer the rigidity of the binding site [ 88 ]. This opened new opportunities for the optimization of the residence time during drug development pipelines.…”

Section: Complementing Static Datamentioning

confidence: 99%

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

Torrens‐Fontanals

Stępniewski

Aranda-García

et al. 2020

IJMS

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G protein-coupled receptors (GPCRs) are implicated in nearly every physiological process in the human body and therefore represent an important drug targeting class. Advances in X-ray crystallography and cryo-electron microscopy (cryo-EM) have provided multiple static structures of GPCRs in complex with various signaling partners. However, GPCR functionality is largely determined by their flexibility and ability to transition between distinct structural conformations. Due to this dynamic nature, a static snapshot does not fully explain the complexity of GPCR signal transduction. Molecular dynamics (MD) simulations offer the opportunity to simulate the structural motions of biological processes at atomic resolution. Thus, this technique can incorporate the missing information on protein flexibility into experimentally solved structures. Here, we review the contribution of MD simulations to complement static structural data and to improve our understanding of GPCR physiology and pharmacology, as well as the challenges that still need to be overcome to reach the full potential of this technique.

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Enhancing Drug Residence Time by Shielding of Intra-Protein Hydrogen Bonds: A Case Study on CCR2 Antagonists

Cited by 15 publications

References 32 publications

In situ crystallography as an emerging method for structure solution of membrane proteins: the case of CCR2A

In situ crystallography as an emerging method for structure solution of membrane proteins: the case of CCR2A

Investigating the Role of the N-Terminal Loop of PD-1 in Binding Process Between PD-1 and Nivolumab via Molecular Dynamics Simulation

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

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