PMID- 34195182
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210702
IS  - 2296-4185 (Print)
IS  - 2296-4185 (Electronic)
IS  - 2296-4185 (Linking)
VI  - 9
DP  - 2021
TI  - De novo Design of G Protein-Coupled Receptor 40 Peptide Agonists for Type 2 
      Diabetes Mellitus Based on Artificial Intelligence and Site-Directed Mutagenesis.
PG  - 694100
LID - 10.3389/fbioe.2021.694100 [doi]
LID - 694100
AB  - G protein-coupled receptor 40 (GPR40), one of the G protein-coupled receptors 
      that are available to sense glucose metabolism, is an attractive target for the 
      treatment of type 2 diabetes mellitus (T2DM). Despite many efforts having been 
      made to discover small-molecule agonists, there is limited research focus on 
      developing peptides acting as GPR40 agonists to treat T2DM. Here, we propose a 
      novel strategy for peptide design to generate and determine potential peptide 
      agonists against GPR40 efficiently. A molecular fingerprint similarity (MFS) 
      model combined with a deep neural network (DNN) and convolutional neural network 
      was applied to predict the activity of peptides constructed by unnatural amino 
      acids (UAAs). Site-directed mutagenesis (SDM) further optimized the peptides to 
      form specific favorable interactions, and subsequent flexible docking showed the 
      details of the binding mechanism between peptides and GPR40. Molecular dynamics 
      (MD) simulations further verified the stability of the peptide-protein complex. 
      The R-square of the machine learning model on the training set and the test set 
      reached 0.87 and 0.75, respectively; and the three candidate peptides showed 
      excellent performance. The strategy based on machine learning and SDM 
      successfully searched for an optimal design with desirable activity comparable 
      with the model agonist in phase III clinical trials.
CI  - Copyright (c) 2021 Chen, Chen, Xu, Lyu, Li, Li, Wang and Wang.
FAU - Chen, Xu
AU  - Chen X
AD  - Department of Pathology, The Eighth Affiliated Hospital, Sun Yat-sen University, 
      Shenzhen, China.
AD  - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 
      China.
FAU - Chen, Zhidong
AU  - Chen Z
AD  - Department of Pathology, The Eighth Affiliated Hospital, Sun Yat-sen University, 
      Shenzhen, China.
AD  - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 
      China.
FAU - Xu, Daiyun
AU  - Xu D
AD  - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 
      China.
FAU - Lyu, Yonghui
AU  - Lyu Y
AD  - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 
      China.
FAU - Li, Yongxiao
AU  - Li Y
AD  - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 
      China.
FAU - Li, Shengbin
AU  - Li S
AD  - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 
      China.
FAU - Wang, Junqing
AU  - Wang J
AD  - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 
      China.
FAU - Wang, Zhe
AU  - Wang Z
AD  - Department of Pathology, The Eighth Affiliated Hospital, Sun Yat-sen University, 
      Shenzhen, China.
LA  - eng
PT  - Journal Article
DEP - 20210614
PL  - Switzerland
TA  - Front Bioeng Biotechnol
JT  - Frontiers in bioengineering and biotechnology
JID - 101632513
PMC - PMC8236607
OTO - NOTNLM
OT  - GPR40
OT  - T2DM
OT  - artificial intelligence
OT  - molecular fingerprint
OT  - oligopeptides
OT  - site-directed mutagenesis
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/07/02 06:00
MHDA- 2021/07/02 06:01
PMCR- 2021/01/01
CRDT- 2021/07/01 07:03
PHST- 2021/04/12 00:00 [received]
PHST- 2021/05/07 00:00 [accepted]
PHST- 2021/07/01 07:03 [entrez]
PHST- 2021/07/02 06:00 [pubmed]
PHST- 2021/07/02 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fbioe.2021.694100 [doi]
PST - epublish
SO  - Front Bioeng Biotechnol. 2021 Jun 14;9:694100. doi: 10.3389/fbioe.2021.694100. 
      eCollection 2021.