PMID- 32575625
OWN - NLM
STAT- MEDLINE
DCOM- 20210218
LR  - 20210218
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 25
IP  - 12
DP  - 2020 Jun 19
TI  - Strategy for Designing Selective Lysosomal Acid alpha-Glucosidase Inhibitors: Binding 
      Orientation and Influence on Selectivity.
LID - 10.3390/molecules25122843 [doi]
LID - 2843
AB  - Deoxynojirimycin (DNJ) is the archetypal iminosugar, in which the configuration 
      of the hydroxyl groups in the piperidine ring truly mimic those of 
      d-glucopyranose; DNJ and derivatives have beneficial effects as therapeutic 
      agents, such as anti-diabetic and antiviral agents, and pharmacological 
      chaperones for genetic disorders, because they have been shown to inhibit 
      alpha-glucosidases from various sources. However, attempts to design a better 
      molecule based solely on structural similarity cannot produce selectivity between 
      alpha-glucosidases that are localized in multiple organs and tissues, because the 
      differences of each sugar-recognition site are very subtle. In this study, we 
      provide the first example of a design strategy for selective lysosomal acid 
      alpha-glucosidase (GAA) inhibitors focusing on the alkyl chain storage site. Our 
      design of alpha-1-C-heptyl-1,4-dideoxy-1,4-imino-l-arabinitol (LAB) produced a potent 
      inhibitor of the GAA, with an IC(50) value of 0.44 microM. It displayed a remarkable 
      selectivity toward GAA (selectivity index value of 168.2). A molecular dynamic 
      simulation study revealed that the ligand-binding conformation stability 
      gradually improved with increasing length of the alpha-1-C-alkyl chain. It is 
      noteworthy that alpha-1-C-heptyl-LAB formed clearly different interactions from DNJ 
      and had favored hydrophobic interactions with Trp481, Phe525, and Met519 at the 
      alkyl chain storage pocket of GAA. Moreover, a molecular docking study revealed 
      that endoplasmic reticulum (ER) alpha-glucosidase II does not have enough space to 
      accommodate these alkyl chains. Therefore, the design strategy focusing on the 
      shape and acceptability of long alkyl chain at each alpha-glucosidase may lead to the 
      creation of more selective and practically useful inhibitors.
FAU - Kato, Atsushi
AU  - Kato A
AUID- ORCID: 0000-0001-8022-196X
AD  - Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
FAU - Nakagome, Izumi
AU  - Nakagome I
AD  - School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
FAU - Hata, Mizuki
AU  - Hata M
AD  - Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
FAU - Nash, Robert J
AU  - Nash RJ
AD  - Institute of Biological, Environmental and Rural Sciences, Plas Gogerddan, 
      Aberystwyth, Ceredigion SY23 3EB, UK.
FAU - Fleet, George W J
AU  - Fleet GWJ
AUID- ORCID: 0000-0003-1903-270X
AD  - Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 
      Oxford OX1 3TA, UK.
FAU - Natori, Yoshihiro
AU  - Natori Y
AD  - Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 
      981-8558, Japan.
FAU - Yoshimura, Yuichi
AU  - Yoshimura Y
AUID- ORCID: 0000-0002-9686-6671
AD  - Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 
      981-8558, Japan.
FAU - Adachi, Isao
AU  - Adachi I
AD  - Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.
FAU - Hirono, Shuichi
AU  - Hirono S
AD  - School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
LA  - eng
GR  - JSPS KAKENHI Grant Number JP17K08362/Japanese Society for the Promotion of 
      Science/
PT  - Journal Article
DEP - 20200619
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Antiviral Agents)
RN  - 0 (Glycoside Hydrolase Inhibitors)
RN  - 0 (Imino Sugars)
RN  - 0 (deoxynojirimycine)
RN  - 19130-96-2 (1-Deoxynojirimycin)
RN  - EC 3.2.1.20 (alpha-Glucosidases)
RN  - N08U5BOQ1K (Glucosamine)
SB  - IM
MH  - 1-Deoxynojirimycin/chemistry
MH  - Antiviral Agents/*chemistry
MH  - *Drug Design
MH  - Glucosamine/analogs & derivatives/chemistry
MH  - Glycoside Hydrolase Inhibitors/*chemistry
MH  - Humans
MH  - Imino Sugars/*chemistry
MH  - *Molecular Docking Simulation
MH  - alpha-Glucosidases/*chemistry
PMC - PMC7357040
OTO - NOTNLM
OT  - ER alpha-glucosidase II
OT  - drug design
OT  - glucosidase inhibitor
OT  - iminosugars
OT  - ligand docking
OT  - lysosomal acid alpha-glucosidase
OT  - molecular dynamics
COIS- The authors declare no conflict of interest.
EDAT- 2020/06/25 06:00
MHDA- 2021/02/20 06:00
PMCR- 2020/06/19
CRDT- 2020/06/25 06:00
PHST- 2020/05/27 00:00 [received]
PHST- 2020/06/12 00:00 [revised]
PHST- 2020/06/18 00:00 [accepted]
PHST- 2020/06/25 06:00 [entrez]
PHST- 2020/06/25 06:00 [pubmed]
PHST- 2021/02/20 06:00 [medline]
PHST- 2020/06/19 00:00 [pmc-release]
AID - molecules25122843 [pii]
AID - molecules-25-02843 [pii]
AID - 10.3390/molecules25122843 [doi]
PST - epublish
SO  - Molecules. 2020 Jun 19;25(12):2843. doi: 10.3390/molecules25122843.