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Scaffold Repurposing Reveals New Nanomolar Phosphodiesterase Type 5 (PDE5) Inhibitors Based on Pyridopyrazinone Scaffold: Investigation of In Vitro and In Silico Properties

Amin, Kamelia M.; El-Badry, Ossama M.; Abdel Rahman, Doaa E.; Abdellattif, Magda H.; Abourehab, Mohammed A. S.; El-Maghrabey, Mahmoud H.; Elsaid, Fahmy G.; El Hamd, Mohamed A.; Elkamhawy, Ahmed; Ammar, Usama M.

Authors

Kamelia M. Amin

Ossama M. El-Badry

Doaa E. Abdel Rahman

Magda H. Abdellattif

Mohammed A. S. Abourehab

Mahmoud H. El-Maghrabey

Fahmy G. Elsaid

Mohamed A. El Hamd

Ahmed Elkamhawy



Abstract

Inhibition of PDE5 results in elevation of cGMP leading to vascular relaxation and reduction in the systemic blood pressure. Therefore, PDE5 inhibitors are used as antihypertensive and antianginal agents in addition to their major use as male erectile dysfunction treatments. Previously, we developed a novel series of 34 pyridopyrazinone derivatives as anticancer agents (series A–H). Herein, a multi-step in silico approach was preliminary conducted to evaluate the predicted PDE5 inhibitory activity, followed by an in vitro biological evaluation over the enzymatic level and a detailed SAR study. The designed 2D-QSAR model which was carried out to predict the IC50 of the tested compounds revealed series B, D, E and G with nanomolar range of IC50 values (6.00–81.56 nM). A further docking simulation model was performed to investigate the binding modes within the active site of PDE5. Interestingly, most of the tested compounds showed almost the same binding modes of that of reported PDE5 inhibitors. To validate the in silico results, an in vitro enzymatic assay over PDE5 enzyme was performed for a number of the promising candidates with different substitutions. Both series E and G exhibited a potent inhibitory activity (IC50 = 18.13–41.41 nM). Compound 11b (series G, oxadiazole-based derivatives with terminal 4-NO2 substituted phenyl ring and rigid linker) was the most potent analogue with IC50 value of 18.13 nM. Structure–activity relationship (SAR) data attained for various substitutions were rationalized. Furthermore, a molecular dynamic simulation gave insights into the inhibitory activity of the most active compound (11b). Accordingly, this report presents a successful scaffold repurposing approach that reveals compound 11b as a highly potent nanomolar PDE5 inhibitor worthy of further investigation.

Journal Article Type Article
Acceptance Date Sep 9, 2022
Online Publication Date Sep 15, 2022
Publication Date Sep 15, 2022
Deposit Date Dec 11, 2022
Publicly Available Date Dec 12, 2022
Journal Pharmaceutics
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 14
Issue 9
Article Number 1954
DOI https://doi.org/10.3390/pharmaceutics14091954
Keywords PDE5 inhibitors; pyridopyrazinone derivatives; scaffold repurposing; in vitro enzyme assay; 2D-QSAR analysis; molecular docking; molecular dynamic simulation
Public URL http://researchrepository.napier.ac.uk/Output/2972445

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