Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors

NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Chao Shen [verfasserIn] Hui Liu [verfasserIn] Xuwen Wang [verfasserIn] Tailong Lei [verfasserIn] Ercheng Wang [verfasserIn] Lei Xu [verfasserIn] Huidong Yu [verfasserIn] Dan Li [verfasserIn] Xiaojun Yao [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	NF-κB inducing kinase NIK inhibitors molecule modeling binding mechanism inhibitor design

Übergeordnetes Werk:	In: Frontiers in Pharmacology - Frontiers Media S.A., 2010, 10(2019)
Übergeordnetes Werk:	volume:10 ; year:2019

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fphar.2019.00345

Katalog-ID:	DOAJ054342406

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allfields	10.3389/fphar.2019.00345 doi (DE-627)DOAJ054342406 (DE-599)DOAJ6cbaf5a72d13478a99b276b6962a8453 DE-627 ger DE-627 rakwb eng RM1-950 Chao Shen verfasserin aut Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors. NF-κB inducing kinase NIK inhibitors molecule modeling binding mechanism inhibitor design Therapeutics. Pharmacology Hui Liu verfasserin aut Xuwen Wang verfasserin aut Tailong Lei verfasserin aut Ercheng Wang verfasserin aut Lei Xu verfasserin aut Huidong Yu verfasserin aut Dan Li verfasserin aut Xiaojun Yao verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 10(2019) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:10 year:2019 https://doi.org/10.3389/fphar.2019.00345 kostenfrei https://doaj.org/article/6cbaf5a72d13478a99b276b6962a8453 kostenfrei https://www.frontiersin.org/article/10.3389/fphar.2019.00345/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
spelling	10.3389/fphar.2019.00345 doi (DE-627)DOAJ054342406 (DE-599)DOAJ6cbaf5a72d13478a99b276b6962a8453 DE-627 ger DE-627 rakwb eng RM1-950 Chao Shen verfasserin aut Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors. NF-κB inducing kinase NIK inhibitors molecule modeling binding mechanism inhibitor design Therapeutics. Pharmacology Hui Liu verfasserin aut Xuwen Wang verfasserin aut Tailong Lei verfasserin aut Ercheng Wang verfasserin aut Lei Xu verfasserin aut Huidong Yu verfasserin aut Dan Li verfasserin aut Xiaojun Yao verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 10(2019) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:10 year:2019 https://doi.org/10.3389/fphar.2019.00345 kostenfrei https://doaj.org/article/6cbaf5a72d13478a99b276b6962a8453 kostenfrei https://www.frontiersin.org/article/10.3389/fphar.2019.00345/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfields_unstemmed	10.3389/fphar.2019.00345 doi (DE-627)DOAJ054342406 (DE-599)DOAJ6cbaf5a72d13478a99b276b6962a8453 DE-627 ger DE-627 rakwb eng RM1-950 Chao Shen verfasserin aut Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors. NF-κB inducing kinase NIK inhibitors molecule modeling binding mechanism inhibitor design Therapeutics. Pharmacology Hui Liu verfasserin aut Xuwen Wang verfasserin aut Tailong Lei verfasserin aut Ercheng Wang verfasserin aut Lei Xu verfasserin aut Huidong Yu verfasserin aut Dan Li verfasserin aut Xiaojun Yao verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 10(2019) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:10 year:2019 https://doi.org/10.3389/fphar.2019.00345 kostenfrei https://doaj.org/article/6cbaf5a72d13478a99b276b6962a8453 kostenfrei https://www.frontiersin.org/article/10.3389/fphar.2019.00345/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfieldsGer	10.3389/fphar.2019.00345 doi (DE-627)DOAJ054342406 (DE-599)DOAJ6cbaf5a72d13478a99b276b6962a8453 DE-627 ger DE-627 rakwb eng RM1-950 Chao Shen verfasserin aut Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors. NF-κB inducing kinase NIK inhibitors molecule modeling binding mechanism inhibitor design Therapeutics. Pharmacology Hui Liu verfasserin aut Xuwen Wang verfasserin aut Tailong Lei verfasserin aut Ercheng Wang verfasserin aut Lei Xu verfasserin aut Huidong Yu verfasserin aut Dan Li verfasserin aut Xiaojun Yao verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 10(2019) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:10 year:2019 https://doi.org/10.3389/fphar.2019.00345 kostenfrei https://doaj.org/article/6cbaf5a72d13478a99b276b6962a8453 kostenfrei https://www.frontiersin.org/article/10.3389/fphar.2019.00345/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfieldsSound	10.3389/fphar.2019.00345 doi (DE-627)DOAJ054342406 (DE-599)DOAJ6cbaf5a72d13478a99b276b6962a8453 DE-627 ger DE-627 rakwb eng RM1-950 Chao Shen verfasserin aut Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors. NF-κB inducing kinase NIK inhibitors molecule modeling binding mechanism inhibitor design Therapeutics. Pharmacology Hui Liu verfasserin aut Xuwen Wang verfasserin aut Tailong Lei verfasserin aut Ercheng Wang verfasserin aut Lei Xu verfasserin aut Huidong Yu verfasserin aut Dan Li verfasserin aut Xiaojun Yao verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 10(2019) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:10 year:2019 https://doi.org/10.3389/fphar.2019.00345 kostenfrei https://doaj.org/article/6cbaf5a72d13478a99b276b6962a8453 kostenfrei https://www.frontiersin.org/article/10.3389/fphar.2019.00345/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
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title	Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors
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title_full	Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors
author_sort	Chao Shen
journal	Frontiers in Pharmacology
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author_browse	Chao Shen Hui Liu Xuwen Wang Tailong Lei Ercheng Wang Lei Xu Huidong Yu Dan Li Xiaojun Yao
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author-letter	Chao Shen
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title_sort	importance of incorporating protein flexibility in molecule modeling: a theoretical study on type i1/2 nik inhibitors
callnumber	RM1-950
title_auth	Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors
abstract	NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors.
abstractGer	NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors.
abstract_unstemmed	NF-κB inducing kinase (NIK), which is considered as the central component of the non-canonical NF-κB pathway, has been proved to be an important target for the regulation of the immune system. In the past few years, NIK inhibitors with various scaffolds have been successively reported, among which type I1/2 inhibitors that can not only bind in the ATP-binding pocket at the DFG-in state but also extend into an additional back pocket, make up the largest proportion of the NIK inhibitors, and are worthy of more attention. In this study, an integration protocol that combines molecule docking, MD simulations, ensemble docking, MM/GB(PB)SA binding free energy calculations, and decomposition was employed to understand the binding mechanism of 21 tricyclic type I1/2 NIK inhibitors. It is found that the docking accuracy is largely dependent on the selection of docking protocols as well as the crystal structures. The predictions given by the ensemble docking based on multiple receptor conformations (MRCs) and the MM/GB(PB)SA calculations based on MD simulations showed higher linear correlations with the experimental data than those given by conventional rigid receptor docking (RRD) methods (Glide, GOLD, and Autodock Vina), highlighting the importance of incorporating protein flexibility in predicting protein–ligand interactions. Further analysis based on MM/GBSA demonstrates that the hydrophobic interactions play the most essential role in the ligand binding to NIK, and the polar interactions also make an important contribution to the NIK-ligand recognition. A deeper comparison of several pairs of representative derivatives reveals that the hydrophobic interactions are vitally important in the structural optimization of analogs as well. Besides, the H-bond interactions with some key residues and the large desolvation effect in the back pocket devote to the affinity distinction. It is expected that our study could provide valuable insights into the design of novel and potent type I1/2 NIK inhibitors.
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title_short	Importance of Incorporating Protein Flexibility in Molecule Modeling: A Theoretical Study on Type I1/2 NIK Inhibitors
url	https://doi.org/10.3389/fphar.2019.00345 https://doaj.org/article/6cbaf5a72d13478a99b276b6962a8453 https://www.frontiersin.org/article/10.3389/fphar.2019.00345/full https://doaj.org/toc/1663-9812
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author2	Hui Liu Xuwen Wang Tailong Lei Ercheng Wang Lei Xu Huidong Yu Dan Li Xiaojun Yao
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up_date	2024-07-03T22:38:46.407Z
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