Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor
A simple, quick, easy and cheap tandem mass spectrometry (MS/MS) method for the determination of adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP) has been newly developed. This novel MS/MS method was applied for the evaluation of the inhibitory effect of a novel 2-oxo-1,2-dihy...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/8/1817 |
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| author | Ilaria Cicalini Barbara De Filippis Nicola Gambacorta Antonio Di Michele Silvia Valentinuzzi Alessandra Ammazzalorso Alice Della Valle Rosa Amoroso Orazio Nicolotti Piero Del Boccio Letizia Giampietro |
| author_facet | Ilaria Cicalini Barbara De Filippis Nicola Gambacorta Antonio Di Michele Silvia Valentinuzzi Alessandra Ammazzalorso Alice Della Valle Rosa Amoroso Orazio Nicolotti Piero Del Boccio Letizia Giampietro |
| author_sort | Ilaria Cicalini |
| collection | DOAJ |
| description | A simple, quick, easy and cheap tandem mass spectrometry (MS/MS) method for the determination of adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP) has been newly developed. This novel MS/MS method was applied for the evaluation of the inhibitory effect of a novel 2-oxo-1,2-dihydropyridine-3-carbonitrile derivative, also named DF492, on PDE3 enzyme activity in comparison to its parent drug milrinone. Molecule DF492, with an IC<sub>50</sub> of 409.5 nM, showed an inhibition of PDE3 greater than milrinone (IC<sub>50</sub> = 703.1 nM). To explain the inhibitory potential of DF492, molecular docking studies toward the human PDE3A were carried out with the aim of predicting the binding mode of DF492. The presence of different bulkier decorating fragments in DF492 was pursued to shift affinity of this novel molecule toward PDE3A compared to milrinone in accordance with both the theoretical and experimental results. The described mass spectrometric approach could have a wider potential use in kinetic and biomedical studies and could be applied for the determination of other phosphodiesterase inhibitor molecules. |
| first_indexed | 2024-03-10T20:26:46Z |
| format | Article |
| id | doaj.art-1221c59e552e4ffb8bd84d2970b06994 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T20:26:46Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-1221c59e552e4ffb8bd84d2970b069942023-11-19T21:41:42ZengMDPI AGMolecules1420-30492020-04-01258181710.3390/molecules25081817Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 InhibitorIlaria Cicalini0Barbara De Filippis1Nicola Gambacorta2Antonio Di Michele3Silvia Valentinuzzi4Alessandra Ammazzalorso5Alice Della Valle6Rosa Amoroso7Orazio Nicolotti8Piero Del Boccio9Letizia Giampietro10Centre of Advanced Studies and Technologies (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Farmacia-Scienze del Farmaco, University “A. Moro” of Bari, 70126 Bari, ItalyDepartment of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyCentre of Advanced Studies and Technologies (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Farmacia-Scienze del Farmaco, University “A. Moro” of Bari, 70126 Bari, ItalyCentre of Advanced Studies and Technologies (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyA simple, quick, easy and cheap tandem mass spectrometry (MS/MS) method for the determination of adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP) has been newly developed. This novel MS/MS method was applied for the evaluation of the inhibitory effect of a novel 2-oxo-1,2-dihydropyridine-3-carbonitrile derivative, also named DF492, on PDE3 enzyme activity in comparison to its parent drug milrinone. Molecule DF492, with an IC<sub>50</sub> of 409.5 nM, showed an inhibition of PDE3 greater than milrinone (IC<sub>50</sub> = 703.1 nM). To explain the inhibitory potential of DF492, molecular docking studies toward the human PDE3A were carried out with the aim of predicting the binding mode of DF492. The presence of different bulkier decorating fragments in DF492 was pursued to shift affinity of this novel molecule toward PDE3A compared to milrinone in accordance with both the theoretical and experimental results. The described mass spectrometric approach could have a wider potential use in kinetic and biomedical studies and could be applied for the determination of other phosphodiesterase inhibitor molecules.https://www.mdpi.com/1420-3049/25/8/1817phosphodiesterases activityAMPcyclic AMPtandem mass spectrometrydihydropyridinedocking studies |
| spellingShingle | Ilaria Cicalini Barbara De Filippis Nicola Gambacorta Antonio Di Michele Silvia Valentinuzzi Alessandra Ammazzalorso Alice Della Valle Rosa Amoroso Orazio Nicolotti Piero Del Boccio Letizia Giampietro Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor Molecules phosphodiesterases activity AMP cyclic AMP tandem mass spectrometry dihydropyridine docking studies |
| title | Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor |
| title_full | Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor |
| title_fullStr | Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor |
| title_full_unstemmed | Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor |
| title_short | Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor |
| title_sort | development of a rapid mass spectrometric determination of amp and cyclic amp for pde3 activity study application and computational analysis for evaluating the effect of a novel 2 oxo 1 2 dihydropyridine 3 carbonitrile derivative as pde 3 inhibitor |
| topic | phosphodiesterases activity AMP cyclic AMP tandem mass spectrometry dihydropyridine docking studies |
| url | https://www.mdpi.com/1420-3049/25/8/1817 |
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