PMID- 31024312
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 10
DP  - 2019
TI  - Importance of Incorporating Protein Flexibility in Molecule Modeling: A 
      Theoretical Study on Type I(1/2) NIK Inhibitors.
PG  - 345
LID - 10.3389/fphar.2019.00345 [doi]
LID - 345
AB  - NF-kappaB inducing kinase (NIK), which is considered as the central component of the 
      non-canonical NF-kappaB 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 I(1/2) 
      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 I(1/2) 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 I(1/2) NIK inhibitors.
FAU - Shen, Chao
AU  - Shen C
AD  - College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
FAU - Liu, Hui
AU  - Liu H
AD  - College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
FAU - Wang, Xuwen
AU  - Wang X
AD  - College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
FAU - Lei, Tailong
AU  - Lei T
AD  - College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
FAU - Wang, Ercheng
AU  - Wang E
AD  - College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
FAU - Xu, Lei
AU  - Xu L
AD  - School of Electrical and Information Engineering, Institute of Bioinformatics and 
      Medical Engineering, Jiangsu University of Technology, Changzhou, China.
FAU - Yu, Huidong
AU  - Yu H
AD  - Rongene Pharma Co., Ltd., Shenzhen, China.
FAU - Li, Dan
AU  - Li D
AD  - College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
FAU - Yao, Xiaojun
AU  - Yao X
AD  - State Key Laboratory of Quality Research in Chinese Medicines, Macau University 
      of Science and Technology, Macau, China.
LA  - eng
PT  - Journal Article
DEP - 20190409
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC6465739
OTO - NOTNLM
OT  - NF-kappaB inducing kinase
OT  - NIK inhibitors
OT  - binding mechanism
OT  - inhibitor design
OT  - molecule modeling
EDAT- 2019/04/27 06:00
MHDA- 2019/04/27 06:01
PMCR- 2019/04/09
CRDT- 2019/04/27 06:00
PHST- 2018/12/22 00:00 [received]
PHST- 2019/03/20 00:00 [accepted]
PHST- 2019/04/27 06:00 [entrez]
PHST- 2019/04/27 06:00 [pubmed]
PHST- 2019/04/27 06:01 [medline]
PHST- 2019/04/09 00:00 [pmc-release]
AID - 10.3389/fphar.2019.00345 [doi]
PST - epublish
SO  - Front Pharmacol. 2019 Apr 9;10:345. doi: 10.3389/fphar.2019.00345. eCollection 
      2019.