PMID- 30381900
OWN - NLM
STAT- MEDLINE
DCOM- 20200115
LR  - 20200115
IS  - 1747-0285 (Electronic)
IS  - 1747-0277 (Linking)
VI  - 93
IP  - 4
DP  - 2019 Apr
TI  - Q817G mutation in phosphodiesterase type 5: Conformational analysis and 
      dissociation profile of the inhibitor Tadalafil.
PG  - 419-429
LID - 10.1111/cbdd.13426 [doi]
AB  - Phosphodiesterase type 5 (PDE-5) is an important enzyme involved in the 
      hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate 
      (GMP). The inhibition of this protein leads to the accumulation of cGMP in cells 
      with various biological and therapeutic effects. Several PDE-5 inhibitors exist, 
      with Tadalafil being one of the most commonly studied and used in clinical 
      therapy. In this study, we applied Molecular Dynamics simulations coupled to the 
      ABF (Adaptive Biasing Force) method to study the effect of the mutation on the 
      Gln817 residue (Q817G). The results of the free energy profiles made clear that 
      the affinity of the inhibitor for PDE-5 is dependent on the amino acid residue 
      Gln817. The hydrogen bond made between the side chain of glutamine and the indole 
      ring of Tadalafil results in the stabilization of the ligand in the catalytic 
      site. Despite the prominent role of this interaction, it is important to 
      highlight the contribution of other residues of the catalytic domain for the 
      stabilization of the compound, due to the set of polar, hydrophobic and 
      electrostatic interactions performed by specific amino acid residues.
CI  - (c) 2018 John Wiley & Sons A/S.
FAU - Pires de Oliveira, Ivan
AU  - Pires de Oliveira I
AD  - Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
FAU - Lescano, Caroline Honaiser
AU  - Lescano CH
AD  - Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
FAU - De Nucci, Gilberto
AU  - De Nucci G
AD  - Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
AD  - Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190219
PL  - England
TA  - Chem Biol Drug Des
JT  - Chemical biology & drug design
JID - 101262549
RN  - 0 (Ligands)
RN  - 0 (Phosphodiesterase 5 Inhibitors)
RN  - 742SXX0ICT (Tadalafil)
RN  - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Binding Sites
MH  - Catalytic Domain
MH  - Cyclic GMP/metabolism
MH  - Cyclic Nucleotide Phosphodiesterases, Type 5/chemistry/genetics/*metabolism
MH  - Humans
MH  - Hydrogen Bonding
MH  - Ligands
MH  - Molecular Dynamics Simulation
MH  - Mutagenesis, Site-Directed
MH  - Phosphodiesterase 5 Inhibitors/*chemistry/metabolism
MH  - Tadalafil/*chemistry/metabolism
MH  - Thermodynamics
OTO - NOTNLM
OT  - PDE-5 inhibitors
OT  - adaptive biasing force
OT  - erectile dysfunction
OT  - molecular dynamic simulations
EDAT- 2018/11/02 06:00
MHDA- 2020/01/16 06:00
CRDT- 2018/11/02 06:00
PHST- 2018/07/06 00:00 [received]
PHST- 2018/10/08 00:00 [revised]
PHST- 2018/10/18 00:00 [accepted]
PHST- 2018/11/02 06:00 [pubmed]
PHST- 2020/01/16 06:00 [medline]
PHST- 2018/11/02 06:00 [entrez]
AID - 10.1111/cbdd.13426 [doi]
PST - ppublish
SO  - Chem Biol Drug Des. 2019 Apr;93(4):419-429. doi: 10.1111/cbdd.13426. Epub 2019 
      Feb 19.