Distinguishing the optimal binding mechanism of an E3 ubiquitin ligase: Covalent versus noncovalent inhibition.
The development of covalent drugs, specifically in cancer therapeutics, has recently sparked interest among the pharmaceutical research community. While representing a significant fraction of the drugs in the market, very few have been deliberately designed to interact covalently with their biological target. One of the enzymes that have been both covalently and noncovalently targeted is the Neural Precursor Cell Expressed Developmentally Downregulated gene 4-1 (Nedd4-1). This enzyme has been found to have multiple physiological implications, including its involvement in cancer invasion. A critical gap still remains in the molecular understanding of the structural mechanism upon the covalent and noncovalent binding to Nedd4-1. In this study, we explore the most optimal binding mechanism in the inhibition of the catalytic site of the Nedd4-1. Our results exhibited a greater stability in the covalent complex compared with the noncovalent complex. This was supported by the secondary structure elements that were more dominant in the covalently inhibited complex. This complex disclosed an optimal free binding energy landscape, induced by the catalytic site energy contributions that showed to be more favorable. The insights demonstrating the above binding mechanism of Nedd4-1 establishes covalent inhibition as the preferred method of inhibition of the enzyme. This investigation aids in the understanding of the structural mechanism of Nedd4-1 inhibition and would assist in the design of more potent covalent inhibitors at the catalytic site of Nedd4-1.
['Bjij|Imane|I|', 'Khan|Shama|S|', 'Ramharak|Pritika|P|', 'Cherqaoui|Driss|D|', 'Soliman|Mahmoud E S|MES|0000-0002-8711-7783']
D001665:Binding Sites D020134:Catalytic Domain D004791:Enzyme Inhibitors D006801:Humans D008958:Models, Molecular D056004:Molecular Dynamics Simulation D000075702:Nedd4 Ubiquitin Protein Ligases D011485:Protein Binding D055550:Protein Stability D017433:Protein Structure, Secondary D013329:Structure-Activity Relationship
noncovalent inhibition Nedd4-1 covalent inhibition MD simulation