PMID- 30917179
OWN - NLM
STAT- MEDLINE
DCOM- 20191216
LR  - 20200309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 14
IP  - 3
DP  - 2019
TI  - Pharmacological and molecular dynamics analyses of differences in inhibitor 
      binding to human and nematode PDE4: Implications for management of parasitic 
      nematodes.
PG  - e0214554
LID - 10.1371/journal.pone.0214554 [doi]
LID - e0214554
AB  - Novel chemical controls are needed that selectively target human, animal, and 
      plant parasitic nematodes with reduced adverse effects on the host or the 
      environment. We hypothesize that the phosphodiesterase (PDE) enzyme family 
      represents a potential target for development of novel nematicides and 
      anthelmintics. To test this, we identified six PDE families present in the 
      nematode phylum that are orthologous to six of the eleven human PDE families. We 
      characterized the binding interactions of family-selective PDE inhibitors with 
      human and C. elegans PDE4 in conjunction with molecular dynamics (MD) simulations 
      to evaluate differences in binding interactions of these inhibitors within the 
      PDE4 catalytic domain. We observed that roflumilast (human PDE4-selective 
      inhibitor) and zardaverine (selective for human PDE3 and PDE4) were 159- and 
      77-fold less potent, respectively, in inhibiting C. elegans PDE4. The 
      pan-specific PDE inhibitor isobutyl methyl xanthine (IBMX) had similar affinity 
      for nematode and human PDE4. Of 32 residues within 5 A of the ligand binding 
      site, five revealed significant differences in non-bonded interaction energies 
      (van der Waals and electrostatic interaction energies) that could account for the 
      differential binding affinities of roflumilast and zardaverine. One site (Phe506 
      in the human PDE4D3 amino acid sequence corresponding to Tyr253 in C. elegans 
      PDE4) is predicted to alter the binding conformation of roflumilast and 
      zardaverine (but not IBMX) into a less energetically favorable state for the 
      nematode enzyme. The pharmacological differences in sensitivity to PDE4 
      inhibitors in conjunction with differences in the amino acids comprising the 
      inhibitor binding sites of human and C. elegans PDE4 catalytic domains together 
      support the feasibility of designing the next generation of 
      anthelmintics/nematicides that could selectively bind to nematode PDEs.
FAU - Schuster, Kevin D
AU  - Schuster KD
AD  - Department of Molecular, Cellular, and Biomedical Sciences, University of New 
      Hampshire, Durham, NH, United States of America.
FAU - Mohammadi, Mohammadjavad
AU  - Mohammadi M
AUID- ORCID: 0000-0001-7344-0857
AD  - Department of Chemical Engineering, University of New Hampshire, Durham, NH, 
      United States of America.
FAU - Cahill, Karyn B
AU  - Cahill KB
AD  - Department of Molecular, Cellular, and Biomedical Sciences, University of New 
      Hampshire, Durham, NH, United States of America.
FAU - Matte, Suzanne L
AU  - Matte SL
AD  - Department of Molecular, Cellular, and Biomedical Sciences, University of New 
      Hampshire, Durham, NH, United States of America.
FAU - Maillet, Alexis D
AU  - Maillet AD
AD  - Department of Molecular, Cellular, and Biomedical Sciences, University of New 
      Hampshire, Durham, NH, United States of America.
FAU - Vashisth, Harish
AU  - Vashisth H
AD  - Department of Chemical Engineering, University of New Hampshire, Durham, NH, 
      United States of America.
FAU - Cote, Rick H
AU  - Cote RH
AUID- ORCID: 0000-0002-1573-6526
AD  - Department of Molecular, Cellular, and Biomedical Sciences, University of New 
      Hampshire, Durham, NH, United States of America.
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190327
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antinematodal Agents)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antinematodal Agents/adverse effects/*metabolism/*pharmacology
MH  - Caenorhabditis elegans/drug effects/*enzymology
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry/*metabolism
MH  - Humans
MH  - *Molecular Dynamics Simulation
MH  - Phosphodiesterase 4 Inhibitors/adverse effects/*metabolism/*pharmacology
MH  - Protein Binding
MH  - Protein Conformation
PMC - PMC6436744
COIS- I have read the journal's policy and the following authors of this manuscript 
      have the following competing interests: Cote, R. H., Cahill, K. B., and Schuster, 
      K. D. (2014). Methods of identification and use of nematicide compounds. PCT 
      Patent Application No. PCT/US14/29910. I affirm that this patent application does 
      not alter our adherence to PLOS ONE policies on sharing data and materials, nor 
      does this patent application interfere with-or could possibly be construed as 
      interfering with-our full and objective presentation of our results.
EDAT- 2019/03/28 06:00
MHDA- 2019/12/18 06:00
PMCR- 2019/03/27
CRDT- 2019/03/28 06:00
PHST- 2019/01/06 00:00 [received]
PHST- 2019/03/14 00:00 [accepted]
PHST- 2019/03/28 06:00 [entrez]
PHST- 2019/03/28 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2019/03/27 00:00 [pmc-release]
AID - PONE-D-19-00429 [pii]
AID - 10.1371/journal.pone.0214554 [doi]
PST - epublish
SO  - PLoS One. 2019 Mar 27;14(3):e0214554. doi: 10.1371/journal.pone.0214554. 
      eCollection 2019.