PMID- 27581752
OWN - NLM
STAT- MEDLINE
DCOM- 20180516
LR  - 20180516
IS  - 1538-0254 (Electronic)
IS  - 0739-1102 (Linking)
VI  - 35
IP  - 13
DP  - 2017 Oct
TI  - In silico design of novel hERG-neutral sildenafil-like PDE5 inhibitors.
PG  - 2830-2852
LID - 10.1080/07391102.2016.1231634 [doi]
AB  - Cyclic nucleotide phosphodiesterase enzymes (PDEs) have functions in regulating 
      the levels of intracellular second messengers, 3', 5'-cyclic adenosine 
      monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), via 
      hydrolysis and decomposing mechanisms in cells. They take essential roles in 
      modulating various cellular activities such as memory and smooth muscle 
      functions. PDE type 5 (PDE5) inhibitors enhance the vasodilatory effects of cGMP 
      in the corpus cavernosum and they are used to treat erectile dysfunction. Patch 
      clamp experiments showed that the IC(50) values of the human 
      ether-a-go-go-related gene (hERG1) potassium (K) ion channel blocking affinity of 
      PDE5 inhibitors sildenafil, vardenafil, and tadalafil as 33, 12, and 100 muM, 
      respectively. hERG1 channel is responsible for the regulation of the action 
      potential of human ventricular myocyte by contributing the rapid component of 
      delayed rectifier K(+) current (I(Kr)) component of the cardiac action potential. 
      In this work, interaction patterns and binding affinity predictions of selected 
      PDE5 inhibitors against the hERG1 channel are studied. It is attempted to develop 
      PDE5 inhibitor analogs with lower binding affinity to hERG1 ion channel while 
      keeping their pharmacological activity against their principal target PDE5 using 
      in silico methods. Based on detailed analyses of docking poses and predicted 
      interaction energies, novel analogs of PDE5 inhibitors with lower predicted 
      binding affinity to hERG1 channels without loosing their principal target 
      activity were proposed. Moreover, molecular dynamics (MD) simulations and 
      post-processing MD analyses (i.e. Molecular Mechanics/Generalized Born Surface 
      Area calculations) were performed. Detailed analysis of molecular simulations 
      helped us to better understand the PDE5 inhibitor-target binding interactions in 
      the atomic level. Results of this study can be useful for designing of novel and 
      safe PDE5 inhibitors with enhanced activity and other tailored properties.
FAU - Kayik, Gulru
AU  - Kayik G
AD  - a Department of Chemistry , Istanbul Technical University , Istanbul 34469 , 
      Turkey.
FAU - Tuzun, Nurcan S
AU  - Tuzun NS
AD  - a Department of Chemistry , Istanbul Technical University , Istanbul 34469 , 
      Turkey.
FAU - Durdagi, Serdar
AU  - Durdagi S
AD  - b Department of Biophysics , School of Medicine, Bahcesehir University , Istanbul 
      , Turkey.
LA  - eng
PT  - Journal Article
DEP - 20161006
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
RN  - 0 (Amino Acids)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Phosphodiesterase 5 Inhibitors)
RN  - BW9B0ZE037 (Sildenafil Citrate)
RN  - E0399OZS9N (Cyclic AMP)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Action Potentials/drug effects
MH  - Amino Acids/metabolism
MH  - Catalytic Domain/physiology
MH  - Cyclic AMP/metabolism
MH  - Cyclic GMP/chemistry
MH  - ERG1 Potassium Channel/*antagonists & inhibitors
MH  - Humans
MH  - Molecular Dynamics Simulation
MH  - Muscle Cells/drug effects/metabolism
MH  - Phosphodiesterase 5 Inhibitors/*chemistry
MH  - Sildenafil Citrate/*chemistry
OTO - NOTNLM
OT  - De Novo design
OT  - MM/GBSA calculations
OT  - PDE5 inhibitors
OT  - hERG1 channel
OT  - molecular docking
OT  - molecular dynamics
OT  - virtual screening
EDAT- 2016/09/02 06:00
MHDA- 2018/05/17 06:00
CRDT- 2016/09/02 06:00
PHST- 2016/09/02 06:00 [pubmed]
PHST- 2018/05/17 06:00 [medline]
PHST- 2016/09/02 06:00 [entrez]
AID - 10.1080/07391102.2016.1231634 [doi]
PST - ppublish
SO  - J Biomol Struct Dyn. 2017 Oct;35(13):2830-2852. doi: 
      10.1080/07391102.2016.1231634. Epub 2016 Oct 6.