In Silico Design of E3 Ubiquitin-Protein Ligase NEDD4-1 Inhibitors: An Alternative Approach for Targeting the MAPK Pathway in Cancer Therapy †
by
and
Davide Pirolli
1, 
Benedetta Righino
2,
Beatrice Tropea
3,
Fiorella Gurrieri
4,
Eugenio Sangiorgi
4 and
Maria Cristina De Rosa
1,* 1
Institute of Chemistry of Molecular Recognition (National Research Council), 00168 Rome, Italy
2
Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, 00168 Rome, Italy
3
Sapienza University of Rome, 00100 Rome, Italy
4
Institute of Genomic Medicine, Catholic University of Rome, 00168 Rome, Italy
*
Author to whom correspondence should be addressed.
†
Presented at the 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery, Barcelona, Spain, 15–17 May 2019.
Proceedings 2019, 22(1), 10; https://doi.org/10.3390/proceedings2019022010
Published: 7 August 2019
(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)
Among all the several targets in common use in the antitumor therapies, the pharmacologic inhibition of the MAPK (Mitogen Activated Protein Kinase) pathway represents an efficient therapeutic approach [1]. The MAPK cascade has a pivotal role in the regulation of the cell cycle and proliferation and, within the framework of this pathway, the Sprouty2 protein (Spry2) has emerged as potential target since it negatively modulates the pathway. The intracellular levels of Spry2, whose reduced expression has been associated to tumors [2,3], are regulated by the E3 ubiquitin-protein ligase, NEDD4-1, that ubiquitinates Spry2 for degradation by the proteasome [4].
This research work focuses on a computer aided drug design aimed to identify small molecules able to inhibit NEDD4-1 activity, to restore the intracellular levels of Spry2, which is downregulated in tumors [2,3,5].
A custom computational strategy was employed in order to identify NEDD4-1 inhibitors, based on a multi-step docking-based virtual screening approach and in silico screening of Maybridge and NCI Diversity Set libraries. The 40 highest-ranking molecules from the virtual screening have been submitted to the experimental validation to evaluate their effective ability to inhibit the catalytic activity of NEDD4-1.
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MDPI and ACS Style
Pirolli, D.; Righino, B.; Tropea, B.; Gurrieri, F.; Sangiorgi, E.; Rosa, M.C.D. In Silico Design of E3 Ubiquitin-Protein Ligase NEDD4-1 Inhibitors: An Alternative Approach for Targeting the MAPK Pathway in Cancer Therapy. Proceedings 2019, 22, 10. https://doi.org/10.3390/proceedings2019022010
AMA Style
Pirolli D, Righino B, Tropea B, Gurrieri F, Sangiorgi E, Rosa MCD. In Silico Design of E3 Ubiquitin-Protein Ligase NEDD4-1 Inhibitors: An Alternative Approach for Targeting the MAPK Pathway in Cancer Therapy. Proceedings. 2019; 22(1):10. https://doi.org/10.3390/proceedings2019022010
Chicago/Turabian StylePirolli, Davide, Benedetta Righino, Beatrice Tropea, Fiorella Gurrieri, Eugenio Sangiorgi, and Maria Cristina De Rosa. 2019. "In Silico Design of E3 Ubiquitin-Protein Ligase NEDD4-1 Inhibitors: An Alternative Approach for Targeting the MAPK Pathway in Cancer Therapy" Proceedings 22, no. 1: 10. https://doi.org/10.3390/proceedings2019022010
