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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.

التفاصيل البيبلوغرافية
العنوان: Scaffold Repurposing Reveals New Nanomolar Phosphodiesterase Type 5 (PDE5) Inhibitors Based on Pyridopyrazinone Scaffold: Investigation of In Vitro and In Silico Properties.
المؤلفون: Amin KM; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., El-Badry OM; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University (ACU), Giza 12566, Egypt., Abdel Rahman DE; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt., Abdellattif MH; Department of Chemistry, College of Science, Taif University, Al-Haweiah, Taif 21944, Saudi Arabia., Abourehab MAS; Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.; Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Minia University, Minia 61519, Egypt., El-Maghrabey MH; Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt., Elsaid FG; Biology Department, Science College, King Khalid University, Abha 61421, Saudi Arabia.; Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt., El Hamd MA; Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.; Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt., Elkamhawy A; BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea.; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt., Ammar UM; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0NR, UK.
المصدر: Pharmaceutics [Pharmaceutics] 2022 Sep 15; Vol. 14 (9). Date of Electronic Publication: 2022 Sep 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101534003 Publication Model: Electronic Cited Medium: Print ISSN: 1999-4923 (Print) Linking ISSN: 19994923 NLM ISO Abbreviation: Pharmaceutics Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI
مستخلص: 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 IC 50 of the tested compounds revealed series B , D , E and G with nanomolar range of IC 50 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 (IC 50 = 18.13-41.41 nM). Compound 11b (series G , oxadiazole-based derivatives with terminal 4-NO 2 substituted phenyl ring and rigid linker) was the most potent analogue with IC 50 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.
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فهرسة مساهمة: Keywords: 2D-QSAR analysis; PDE5 inhibitors; in vitro enzyme assay; molecular docking; molecular dynamic simulation; pyridopyrazinone derivatives; scaffold repurposing
تواريخ الأحداث: Date Created: 20220923 Latest Revision: 20220928
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC9501832
DOI: 10.3390/pharmaceutics14091954
PMID: 36145702
قاعدة البيانات: MEDLINE
الوصف
تدمد:1999-4923
DOI:10.3390/pharmaceutics14091954