PMID- 32794708
OWN - NLM
STAT- MEDLINE
DCOM- 20201218
LR  - 20201218
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 63
IP  - 17
DP  - 2020 Sep 10
TI  - Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting 
      a Unique Allosteric Pocket.
PG  - 9828-9837
LID - 10.1021/acs.jmedchem.0c00983 [doi]
AB  - Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side 
      effects due to weak isoform selectivity. Herein, a unique allosteric pocket of 
      PDE5 is identified by molecular modeling and structural biology, which enables 
      the discovery of highly selective PDE5 inhibitors from natural product evodiamine 
      (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed 
      that binding of (S)-7e to the novel allosteric pocket induced dramatic 
      conformation changes in the H-loop with a maximum 24 A movement of their Calpha 
      atoms. This movement directly blocks the binding of substrate/inhibitors to the 
      PDE5 active site, which is different from all traditional PDE5 inhibitors such as 
      sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold 
      selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective 
      treatment of pulmonary hypertension in vivo.
FAU - Zhang, Tianhua
AU  - Zhang T
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. 
      R. China.
AD  - Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer 
      Center, The University of North Carolina, Chapel Hill, North Carolina 27599-7260, 
      United States.
FAU - Lai, Zengwei
AU  - Lai Z
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. 
      R. China.
AD  - School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 
      200433, China.
FAU - Yuan, Suying
AU  - Yuan S
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. 
      R. China.
FAU - Huang, Yi-You
AU  - Huang YY
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. 
      R. China.
FAU - Dong, Guoqiang
AU  - Dong G
AD  - School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 
      200433, China.
FAU - Sheng, Chunquan
AU  - Sheng C
AUID- ORCID: 0000-0001-9489-804X
AD  - School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 
      200433, China.
FAU - Ke, Hengming
AU  - Ke H
AD  - Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer 
      Center, The University of North Carolina, Chapel Hill, North Carolina 27599-7260, 
      United States.
FAU - Luo, Hai-Bin
AU  - Luo HB
AUID- ORCID: 0000-0002-2163-0509
AD  - School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. 
      R. China.
AD  - Key Laboratory of Tropical Biological Resources of Ministry of Education, School 
      of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, Hainan, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200827
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Phosphodiesterase 5 Inhibitors)
RN  - 0 (Quinazolines)
RN  - C01825BVNL (evodiamine)
RN  - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5)
RN  - EC 3.1.4.35 (Pde5a protein, mouse)
SB  - IM
MH  - Allosteric Site
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cyclic Nucleotide Phosphodiesterases, Type 5/chemistry/*metabolism
MH  - Drug Discovery
MH  - Male
MH  - Mice
MH  - Molecular Docking Simulation
MH  - Phosphodiesterase 5 Inhibitors/chemistry/*metabolism/pharmacokinetics
MH  - Protein Binding
MH  - Quinazolines/chemistry/*metabolism/pharmacokinetics
MH  - Rats, Sprague-Dawley
MH  - Sequence Alignment
MH  - Structure-Activity Relationship
EDAT- 2020/08/17 06:00
MHDA- 2020/12/19 06:00
CRDT- 2020/08/16 06:00
PHST- 2020/08/17 06:00 [pubmed]
PHST- 2020/12/19 06:00 [medline]
PHST- 2020/08/16 06:00 [entrez]
AID - 10.1021/acs.jmedchem.0c00983 [doi]
PST - ppublish
SO  - J Med Chem. 2020 Sep 10;63(17):9828-9837. doi: 10.1021/acs.jmedchem.0c00983. Epub 
      2020 Aug 27.