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. 2021 May 10;11(5):709.
doi: 10.3390/biom11050709.

Computational Study on Selective PDE9 Inhibitors on PDE9-Mg/Mg, PDE9-Zn/Mg, and PDE9-Zn/Zn Systems

Dakshinamurthy Sivakumar  1 , Sathishkumar Mudedla  1 , Seonghun Jang  1 , Hyunjun Kim  2 , Hyunjin Park  2 , Yonwon Choi  2 , Joongyo Oh  2 , Sangwook Wu  1
Affiliations

Computational Study on Selective PDE9 Inhibitors on PDE9-Mg/Mg, PDE9-Zn/Mg, and PDE9-Zn/Zn Systems

Dakshinamurthy Sivakumar et al. Biomolecules. .

Abstract

PDE9 inhibitors have been studied to validate their potential to treat diabetes, neurodegenerative disorders, cardiovascular diseases, and erectile dysfunction. In this report, we have selected highly potent previously reported selective PDE9 inhibitors BAY73-6691R, BAY73-6691S, 28r, 28s, 3r, 3s, PF-0447943, PF-4181366, and 4r to elucidate the differences in their interaction patterns in the presence of different metal systems such as Zn/Mg, Mg/Mg, and Zn/Zn. The initial complexes were generated by molecular docking followed by molecular dynamics simulation for 100 ns in triplicate for each system to understand the interactions' stability. The results were carefully analyzed, focusing on the ligands' non-bonded interactions with PDE9 in different metal systems.

Keywords: BAY73-6691; PDE9; metal complexes; molecular dynamics; selective inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Selected literature reported chemical structures of PDE9 inhibitors [18]. Compound 1 (BAY73-6691), Compound 2 (28r and 28s), Compound 3 (3r and 3s), Compound 4 (PF-04447943), Compound 5 (PF-4181366), and Compound 6 (4r). The chiral carbon that makes two enantiomers were marked with symbol (*). Common substructure included separately with numbering.
Figure 2
Figure 2
Non-bonded interactions of Compound 1(R) in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 3
Figure 3
The strength of the hydrogen bond interactions between the critical residues of PDE-9 (in Zn/Mg, Mg/Mg, and Zn/Zn) and the compounds was monitored throughout the simulations.
Figure 4
Figure 4
Non-bonded interactions of Compound 1(S) in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 5
Figure 5
Non-bonded interactions of Compound 2 (R) in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 6
Figure 6
Non-bonded interactions of Compound 2(S) in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 7
Figure 7
Non-bonded interactions of Compound 3(R) in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 8
Figure 8
Non-bonded interactions of Compound 3 (S) in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 9
Figure 9
Non-bonded interactions of Compound 4 in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 10
Figure 10
Non-bonded interactions of Compound 5 in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 11
Figure 11
Non-bonded interactions of Compound 6 in (A) PDE9 Zn/Mg (B) PDE9 Mg/Mg (C) PDE9 Zn/Zn.
Figure 12
Figure 12
MD interaction energy was calculated for the compounds in PDE-9 (in Zn/Mg, Mg/Mg, and Zn/Zn).
Figure 13
Figure 13
MM-PBSA binding free energy was calculated for the compounds in different metal systems.
See this image and copyright information in PMC

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